Inhibitors of glucocorticoid receptor

ABSTRACT

The present invention relates generally to compositions and methods for treating cancer and hypercortisolism. Provided herein are substituted steroidal derivative compounds and pharmaceutical compositions comprising said compounds. The subject compounds and compositions are useful for inhibition of glucocorticoid receptors. Furthermore, the subject compounds and compositions are useful for the treatment of cancer.

CROSS REFERENCE

This application is a continuation of Ser. No. 17/039,794, filed Sep.30, 2020, which is a continuation of U.S. application Ser. No.16/889,624, filed Jun. 1, 2020, now U.S. Pat. No. 10,836,789, issuedNov. 17, 2020, which is a continuation of U.S. application Ser. No.16/562,204, filed Sep. 5, 2019, now U.S. Pat. No. 10,723,759, issuedJul. 28, 2020, which is a division of U.S. application Ser. No.16/365,422, filed Mar. 26, 2019, now U.S. Pat. No. 10,472,387, issuedNov. 12, 2019, which is a continuation of PCT International ApplicationNo. PCT/US2017/055660, filed Oct. 6, 2017, which claims the benefit ofU.S. Application Ser. No. 62/526,331, filed Jun. 28, 2017, and U.S.Application Ser. No. 62/405,801 fled Oct. 7, 2016, each of which arehereby incorporated by reference in their entirety.

BACKGROUND

A need exists in the art for an effective treatment of cancer,neoplastic disease, and hypercortisolism.

BRIEF SUMMARY OF THE INVENTION

Provided herein are substituted steroidal derivative compounds andpharmaceutical compositions comprising said compounds. The subjectcompounds and compositions are useful as inhibitors of glucocorticoidreceptors (GR). Furthermore, the subject compounds and compositions areuseful for the treatment of cancer, such as prostate cancer, breastcancer, lung cancer, and ovarian cancer, and hypercortisolism.

Some embodiments provided herein describe compounds having the structureof Formula (III), or a pharmaceutically acceptable salt, solvate, orprodrug thereof:

wherein

-   ring A is a heteroaryl, aryl, cycloalkyl, or heterocyclyl;-   R¹ is —NR^(4a)R^(5a);-   each R² is independently —NR⁴R⁵, optionally substituted alkylNR⁴R⁵,    halo, —OR⁶, —OH, optionally substituted alkyl, haloalkyl, optionally    substituted carbocyclyl, optionally substituted carbocyclylalkyl,    optionally substituted heteroalkyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, optionally    substituted hydroxyalkyl, —C(O)R⁶, —C(O)OR⁶, —C(O)NR⁴R⁵, —OC(O)OR⁶,    —OC(O)NR⁴R⁵, —S(O)₂NR⁴R⁵, —S(O)₂R⁷, —S(O)R⁷, —SR⁷, —NR⁴S(O)₂NR⁴R⁵,    —CN, —CO₂H, or —NO₂;-   or R¹ and R² on adjacent atoms are taken together with the atoms to    which they are attached to form an optionally substituted    heterocycle;-   R³ is optionally substituted C₂₋₈ alkyl, halo, haloalkyl, optionally    substituted carbocyclyl, optionally substituted carbocyclylalkyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heteroalkyl, optionally    substituted aryl, optionally substituted heteroaryl, —Si(R⁶)₃, —OR⁶,    or —S(O)₂R⁷;-   R^(4a) is C₂₋₈ alkyl, optionally substituted carbocyclyl, optionally    substituted aryl, optionally substituted heterocyclyl, optionally    substituted heteroaryl, —S(O)R⁷, —C(O)N(R¹³)₂, —C(O)R⁶, or —C(O)OR⁶;-   R^(5a) is —H, optionally substituted alkyl, haloalkyl, optionally    substituted carbocyclyl, optionally substituted aryl, optionally    substituted heterocyclyl, optionally substituted heteroaryl,    —S(O)₂R⁷, —C(O)N(R¹³)₂, —C(O)R⁶, or —C(O)OR⁶;-   or R^(4a) and R^(5a) are taken together with the N atom to which    they are attached to form an optionally substituted heterocycle;-   R⁴ and R⁵ are each independently —H, optionally substituted alkyl,    haloalkyl, optionally substituted carbocyclyl, optionally    substituted aryl, optionally substituted heterocyclyl, optionally    substituted heteroaryl, —S(O)₂R⁷, —C(O)N(R¹³)₂, —C(O)R⁶, or    —C(O)OR⁶;-   or R⁴ and R⁵ are taken together with the N atom to which they are    attached to form a substituted or unsubstituted heterocycle;-   each R⁶ is independently optionally substituted alkyl, haloalkyl,    optionally substituted carbocyclyl, optionally substituted aryl,    optionally substituted heterocyclyl, or optionally substituted    heteroaryl;-   R⁷ is optionally substituted alkyl, haloalkyl, optionally    substituted carbocyclyl, optionally substituted heteroalkyl,    optionally substituted aryl, optionally substituted aralkyl,    optionally substituted heterocyclyl, or optionally substituted    heteroaryl;-   R⁸ and R⁹ are each independently —H, optionally substituted alkyl,    haloalkyl, halo, optionally substituted carbocyclyl, optionally    substituted carbocyclylalkyl, optionally substituted heteroalkyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, —OH, —S(O)₂R⁷, —C(O)₂H, —C(O)R⁶, or —C(O)OR⁶;-   or R⁸ and R⁹ are taken together with the atom to which they are    attached to form a substituted or unsubstituted ring containing 0-2    heteroatoms selected from the group consisting of —O—, —NH—, —NR⁶—,    —S—, and —S(O)₂—;-   R¹⁰ and R¹¹ are each independently —H, optionally substituted alkyl,    halo, haloalkyl, optionally substituted carbocyclyl, optionally    substituted carbocyclylalkyl, optionally substituted heteroalkyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, —OH, —S(O)₂R⁷, —C(O)₂H, —C(O)R⁶, or —C(O)OR⁶;-   or R¹⁰ and R¹¹ are taken together with the atom to which they are    attached to form a substituted or unsubstituted ring containing 0-2    heteroatoms selected from the group consisting of —O—, —NH—, —NR⁶—,    —S—, and —S(O)₂—;-   R¹² is hydrogen, optionally substituted alkyl, haloalkyl, hydroxy,    halo, optionally substituted carbocyclyl, optionally substituted    carbocyclylalkyl, optionally substituted heterocyclyl, optionally    substituted heterocyclylalkyl, or optionally substituted    heteroalkyl;-   each R¹³ is independently H, optionally substituted alkyl,    haloalkyl, optionally substituted carbocyclyl, optionally    substituted heteroalkyl, optionally substituted aryl, optionally    substituted aralkyl, optionally substituted heterocyclyl, or    optionally substituted heteroaryl; and-   n is 0, 1, 2, 3, or 4.

In some embodiments of a compound of Formula (III), or apharmaceutically acceptable salt, solvate, or prodrug thereof, R¹² ishydrogen, alkyl, haloalkyl, hydroxy, halo, carbocyclyl, or heteroalkyl.In some embodiments of a compound of Formula (III), or apharmaceutically acceptable salt, solvate, or prodrug thereof, R¹² isC₁₋₆ alkyl or hydrogen. In some embodiments of a compound of Formula(III), or a pharmaceutically acceptable salt, solvate, or prodrugthereof, R¹² is methyl. In some embodiments of a compound of Formula(III), or a pharmaceutically acceptable salt, solvate, or prodrugthereof, R¹² is H. In some embodiments of a compound of Formula (III),or a pharmaceutically acceptable salt, solvate, or prodrug thereof, ringA is monocyclic heteroaryl or monocyclic aryl. In some embodiments of acompound of Formula (III), or a pharmaceutically acceptable salt,solvate, or prodrug thereof, ring A is phenyl, pyridinyl, pyrimidinyl,pyrazinyl, or pyridazinyl. In some embodiments of a compound of Formula(III), or a pharmaceutically acceptable salt, solvate, or prodrugthereof, ring A is phenyl. In some embodiments of a compound of Formula(III), or a pharmaceutically acceptable salt, solvate, or prodrugthereof, R^(4a) is C₂₋₈ alkyl. In some embodiments of a compound ofFormula (III), or a pharmaceutically acceptable salt, solvate, orprodrug thereof, R^(4a) is C₃₋₆ alkyl. In some embodiments of a compoundof Formula (III), or a pharmaceutically acceptable salt, solvate, orprodrug thereof, R^(4a) is C₂₋₄ alkyl. In some embodiments of a compoundof Formula (III), or a pharmaceutically acceptable salt, solvate, orprodrug thereof, R^(4a) is ethyl, i-propyl, or t-butyl. In someembodiments of a compound of Formula (III), or a pharmaceuticallyacceptable salt, solvate, or prodrug thereof, R^(5a) is —H, optionallysubstituted alkyl, or haloalkyl. In some embodiments of a compound ofFormula (III), or a pharmaceutically acceptable salt, solvate, orprodrug thereof, R^(5a) is —H or alkyl. In some embodiments of acompound of Formula (III), or a pharmaceutically acceptable salt,solvate, or prodrug thereof, R^(5a) is C₁₋₆ alkyl. In some embodimentsof a compound of Formula (III), or a pharmaceutically acceptable salt,solvate, or prodrug thereof, R^(4a) and R^(5a) are taken together withthe N atom to which they are attached to form an optionally substitutedheterocycle. In some embodiments of a compound of Formula (III), or apharmaceutically acceptable salt, solvate, or prodrug thereof, R^(4a)and R^(5a) are taken together with the N atom to which they are attachedto form an optionally substituted pyrrolidinyl, an optionallysubstituted morpholinyl, an optionally substituted thiomorpholinyl, anoptionally substituted piperidinyl, or an optionally substitutedpiperazinyl. In some embodiments of a compound of Formula (III), or apharmaceutically acceptable salt, solvate, or prodrug thereof, n is 0,1, or 2. In some embodiments of a compound of Formula (III), or apharmaceutically acceptable salt, solvate, or prodrug thereof, n is 0.In some embodiments of a compound of Formula (III), or apharmaceutically acceptable salt, solvate, or prodrug thereof, n is 1.

In some embodiments of a compound of Formula (III), or apharmaceutically acceptable salt, solvate, or prodrug thereof, each R²is independently —NR⁴R⁵, halo, —OR⁶, alkyl, fluoroalkyl, carbocyclyl,heteroalkyl, heterocyclyl, —S(O)₂NR⁴R⁵, or —S(O)₂R⁷. In some embodimentsof a compound of Formula (III), or a pharmaceutically acceptable salt,solvate, or prodrug thereof, R³ is optionally substituted C₂₋₈ alkyl,haloalkyl, or optionally substituted carbocyclyl. In some embodiments ofa compound of Formula (III), or a pharmaceutically acceptable salt,solvate, or prodrug thereof, R³ is C₄₋₈ alkyl, haloalkyl, or optionallysubstituted carbocyclyl. In some embodiments of a compound of Formula(III), or a pharmaceutically acceptable salt, solvate, or prodrugthereof, R³ is CF₃, t-butyl, or cyclopropyl. In some embodiments of acompound of Formula (III), or a pharmaceutically acceptable salt,solvate, or prodrug thereof, R³ is C₄₋₈ alkyl. In some embodiments of acompound of Formula (III), or a pharmaceutically acceptable salt,solvate, or prodrug thereof, R³ is t-butyl. In some embodiments of acompound of Formula (III), or a pharmaceutically acceptable salt,solvate, or prodrug thereof, R³ is haloalkyl. In some embodiments of acompound of Formula (III), or a pharmaceutically acceptable salt,solvate, or prodrug thereof, R³ is CF₃. In some embodiments of acompound of Formula (III), or a pharmaceutically acceptable salt,solvate, or prodrug thereof, R³ is optionally substituted carbocyclyl.In some embodiments of a compound of Formula (III), or apharmaceutically acceptable salt, solvate, or prodrug thereof, R³ iscyclopropyl. In some embodiments of a compound of Formula (III), or apharmaceutically acceptable salt, solvate, or prodrug thereof, R⁸ and R⁹are each independently —H, alkyl, or carbocyclyl. In some embodiments ofa compound of Formula (III), or a pharmaceutically acceptable salt,solvate, or prodrug thereof, R⁸ and R⁹ are —H. In some embodiments of acompound of Formula (III), or a pharmaceutically acceptable salt,solvate, or prodrug thereof, R¹⁰ and R¹¹ are each independently —H, C₁₋₆alkyl, halo, C₁₋₆ alkoxy, or —OH. In some embodiments of a compound ofFormula (III), or a pharmaceutically acceptable salt, solvate, or produgthereof, R¹⁰ and R¹¹ are each —H. In some embodiments of a compound ofFormula (III), or a pharmaceutically acceptable salt, solvate, orprodrug thereof, R¹⁰ and R¹¹ are taken together with the atom to whichthey are attached to form a 3-, 4-, 5-, or 6-membered ring. In someembodiments of a compound of Formula (III), or a pharmaceuticallyacceptable salt, solvate, or prodrug thereof, R⁴ and R⁵ are eachindependently —H, C₁₋₆ alkyl, or —S(O)₂R⁷. In some embodiments of acompound of Formula (III), or a pharmaceutically acceptable salt,solvate, or prodrug thereof, R⁴ and R⁵ attached to the same N atom aretaken together with the N atom to which they are attached to form asubstituted or unsubstituted 4-, 5-, or 6-membered ring heterocycleadditionally containing 0-3 heteroatoms selected from the groupconsisting of —O—, —NH—, —NR⁶—, —S—, and —S(O)₂—. In some embodiments ofa compound of Formula (III), or a pharmaceutically acceptable salt,solvate, or prodrug thereof, R⁶ is alkyl, carbocyclyl, or fluoroalkyl.In some embodiments of a compound of Formula (III), or apharmaceutically acceptable salt, solvate, or prodrug thereof, R⁷ isalkyl, carbocyclyl, optionally substituted aryl, optionally substitutedaralkyl, or optionally substituted heterocyclyl.

In some embodiments of a compound of Formula (III), or apharmaceutically acceptable salt, solvate, or prodrug thereof, thecompound has the structure of Formula (IIIa):

Some embodiments provided herein describe a pharmaceutical compositioncomprising a pharmaceutically acceptable excipient and a compound ofFormula (III) or (IIIa), or a pharmaceutically acceptable salt, solvate,or prodrug thereof.

Also provided herein are methods for treating or preventing cancer in asubject, the method comprising administering to the subject atherapeutically effective amount of a compound having the structure ofFormula (III) or (IIIa), or a pharmaceutically acceptable salt, solvate,or prodrug thereof. Also provided herein are methods for reducingincidences of cancer recurrence, the method comprising administering toa subject in cancer remission a therapeutically effective amount of acompound having the structure of Formula (III) or (IIIa), or apharmaceutically acceptable salt, solvate, or prodrug thereof. Someembodiments provided herein describe methods for treating achemo-resistant cancer in a subject, the method comprising administeringto the subject a therapeutically effective amount of a compound havingthe structure of Formula (III) or (IIIa), or a pharmaceuticallyacceptable salt, solvate, or prodrug thereof.

In some embodiments, the cancer is triple negative breast cancer, highgrade serous ovarian cancer, castration resistant prostate cancer, ordoubly resistant prostate cancer. In some embodiments, the cancer isnon-small cell lung cancer. In some embodiments, the methods furthercomprise administering a second therapeutic agent to the subject. Insome embodiments, the methods further comprise administering one or moreadditional therapeutic agents. In some embodiments, the second oradditional therapeutic agent is an androgen receptor signalinginhibitor. In specific embodiments, the androgen receptor signalinginhibitor is 3,3′-diindolylmethane (DIM), abiraterone acetate, ARN-509,bexlosteride, bicalutamide, dutasteride, epristeride, enzalutamide,finasteride, flutamide, izonsteride, ketoconazole,N-butylbenzene-sulfonamide, nilutamide, megestrol, steroidalantiandrogens, turosteride, or any combination thereof. In someembodiments, the second or additional therapeutic agent is achemotherapeutic agent. In other embodiments, the second or additionaltherapeutic agent is cisplatin, carboplatin, paclitaxel, gemcitabine,doxorubicin, camptothecin, topotecan, or any combinations thereof. Insome embodiments, the second or additional therapeutic agent is animmunotherapy agent (e.g., an anti-PD-L1 agent or an anti-PD1 agent). Incertain embodiments, the second or additional therapeutic agent is ananti-PD-L1 agent. In certain embodiments, the second or additionaltherapeutic agent is an anti-PD1 agent.

Other embodiments provided herein describe methods for treating ahypercortisolism disease or disorder in a subject, the method comprisingadministering to the subject in need thereof a therapeutically effectiveamount of a compound having the structure of Formula (III) or (IIIa), ora pharmaceutically acceptable salt, solvate, or prodrug thereof. Incertain embodiments, the hypercortisolism disease or disorder isCushing's syndrome. In certain embodiments, the hypercortisolism diseaseor disorder is refractory Cushing's syndrome.

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in thisspecification are herein incorporated by reference for the specificpurposes identified herein.

DETAILED DESCRIPTION OF THE INVENTION

As used herein and in the appended claims, the singular forms “a,”“and,” and “the” include plural referents unless the context clearlydictates otherwise. Thus, for example, reference to “an agent” includesa plurality of such agents, and reference to “the cell” includesreference to one or more cells (or to a plurality of cells) andequivalents thereof known to those skilled in the art, and so forth.When ranges are used herein for physical properties, such as molecularweight, or chemical properties, such as chemical formulae, allcombinations and subcombinations of ranges and specific embodimentstherein are intended to be included. The term “about” when referring toa number or a numerical range means that the number or numerical rangereferred to is an approximation within experimental variability (orwithin statistical experimental error), and thus the number or numericalrange, in some instances, will vary between 1% and 15% of the statednumber or numerical range. The term “comprising” (and related terms suchas “comprise” or “comprises” or “having” or “including”) is not intendedto exclude that in other certain embodiments, for example, an embodimentof any composition of matter, composition, method, or process, or thelike, described herein, “consist of” or “consist essentially of” thedescribed features.

Definitions

As used in the specification and appended claims, unless specified tothe contrary, the following terms have the meaning indicated below.

“Amino” refers to the —NH₂ radical.

“Cyano” refers to the —CN radical.

“Nitro” refers to the —NO₂ radical.

“Oxa” refers to the —O— radical.

“Oxo” refers to the ═O radical.

“Thioxo” refers to the ═S radical.

“Imino” refers to the ═N—H radical.

“Oximo” refers to the ═N—OH radical.

“Hydrazino” refers to the ═N—NH₂ radical.

“Alkyl” refers to a straight or branched hydrocarbon chain radicalconsisting solely of carbon and hydrogen atoms, containing nounsaturation, having from one to fifteen carbon atoms (e.g., C₁-C₁₅alkyl). In certain embodiments, an alkyl comprises one to thirteencarbon atoms (e.g., C₁-C₁₃ alkyl). In certain embodiments, an alkylcomprises one to eight carbon atoms (e.g., C₁-C₈ alkyl). In otherembodiments, an alkyl comprises one to five carbon atoms (e.g., C₁-C₅alkyl). In other embodiments, an alkyl comprises one to four carbonatoms (e.g., C₁-C₄ alkyl). In other embodiments, an alkyl comprises oneto three carbon atoms (e.g., C₁-C₃ alkyl). In other embodiments, analkyl comprises one to two carbon atoms (e.g., C₁-C₂ alkyl). In otherembodiments, an alkyl comprises one carbon atom (e.g., C₁ alkyl). Inother embodiments, an alkyl comprises five to fifteen carbon atoms(e.g., C₅-C₁₅ alkyl). In other embodiments, an alkyl comprises five toeight carbon atoms (e.g., C₅-C₈ alkyl). In other embodiments, an alkylcomprises two to five carbon atoms (e.g., C₂-C₅ alkyl). In otherembodiments, an alkyl comprises three to five carbon atoms (e.g.,C₃-C₅alkyl). In other embodiments, the alkyl group is selected frommethyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (iso-propyl), 1-butyl(n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl),1,1-dimethylethyl (tert-butyl), 1-pentyl (n-pentyl). The alkyl isattached to the rest of the molecule by a single bond. Unless statedotherwise specifically in the specification, an alkyl group isoptionally substituted by one or more of the following substituents:halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl,—OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a),—C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a), —OC(O) N(R^(a)),—N(R^(a))C(O)R^(a), —N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2),—S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)R^(a) (where t is 1 or 2)and —S(O)_(t)N(R^(a))₂ (where t is 1 or 2) where each R^(a) isindependently hydrogen, alkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), carbocyclylalkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl),heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), heterocyclylalkyl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl), orheteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy,or trifluoromethyl).

“Alkoxy” refers to a radical bonded through an oxygen atom of theformula —O-alkyl, where alkyl is an alkyl chain as defined above.

“Alkenyl” refers to a straight or branched hydrocarbon chain radicalgroup consisting solely of carbon and hydrogen atoms, containing atleast one carbon-carbon double bond, and having from two to twelvecarbon atoms. In certain embodiments, an alkenyl comprises two to eightcarbon atoms. In other embodiments, an alkenyl comprises two to fourcarbon atoms. The alkenyl is attached to the rest of the molecule by asingle bond, for example, ethenyl (i.e., vinyl), prop-1-enyl (i.e.,allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like. Unlessstated otherwise specifically in the specification, an alkenyl group isoptionally substituted by one or more of the following substituents:halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl,—OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a),—C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a), —OC(O)—N(R^(a))₂,—N(R^(a))C(O)R^(a), —N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2),—S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)R^(a) (where t is 1 or 2)and —S(O)_(t)N(R^(a))₂ (where t is 1 or 2) where each R^(a) isindependently hydrogen, alkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), carbocyclylalkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl),heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), heterocyclylalkyl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl), orheteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy,or trifluoromethyl).

“Alkynyl” refers to a straight or branched hydrocarbon chain radicalgroup consisting solely of carbon and hydrogen atoms, containing atleast one carbon-carbon triple bond, having fun two to twelve carbonatoms. In certain embodiments, an alkynyl comprises two to eight carbonatoms. In other embodiments, an alkynyl comprises two to six carbonatoms. In other embodiments, an alkynyl comprises two to four carbonatoms. The alkynyl is attached to the rest of the molecule by a singlebond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, andthe like. Unless stated otherwise specifically in the specification, analkynyl group is optionally substituted by one or more of the followingsubstituents: halo, cyano, nitro, oxo, thioxo, imino, oximo,trimethylsilanyl, —OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂,—C(O)R^(a), —C(O)OR^(a), —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a),—OC(O)—N(R^(a))₂, —N(R^(a))C(O)R^(a), —N(R^(a))S(O)_(t)R^(a) (where t is1 or 2), —S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)R^(a) (where t is1 or 2) and —S(O)_(t)N(R^(a))₂ (where t is 1 or 2) where each R^(a) isindependently hydrogen, alkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), carbocyclylalkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl),heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), heterocyclylalkyl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl), orheteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy,or trifluoromethyl).

“Alkylene” or “alkylene chain” refers to a straight or branched divalenthydrocarbon chain linking the rest of the molecule to a radical group,consisting solely of carbon and hydrogen, containing no unsaturation andhaving from one to twelve carbon atoms, for example, methylene,ethylene, propylene, n-butylene, and the like. The alkylene chain isattached to the rest of the molecule through a single bond and to theradical group through a single bond. The points of attachment of thealkylene chain to the rest of the molecule and to the radical group isthrough one carbon in the alkylene chain or through any two carbonswithin the chain. In certain embodiments, an alkylene comprises one toeight carbon atoms (e.g., C₁-C₈ alkylene). In other embodiments, analkylene comprises one to five carbon atoms (e.g., C₁-C₅ alkylene). Inother embodiments, an alkylene comprises one to four carbon atoms (e.g.,C₁-C₄ alkylene). In other embodiments, an alkylene comprises one tothree carbon atoms (e.g., C₁-C₃ alkylene). In other embodiments, analkylene comprises one to two carbon atoms (e.g., C₁-C₂ alkylene). Inother embodiments, an alkylene comprises one carbon atom (e.g., C₁alkylene). In other embodiments, an alkylene comprises five to eightcarbon atoms (e.g., C₅-C₈ alkylene). In other embodiments, an alkylenecomprises two to five carbon atoms (e.g., C₂-C₅ alkylene). In otherembodiments, an alkylene comprises three to five carbon atoms (e.g.,C₃-C₅ alkylene). Unless stated otherwise specifically in thespecification, an alkylene chain is optionally substituted by one ormore of the following substituents: halo, cyano, nitro, oxo, thioxo,imino, oximo, trimethylsilanyl, —OR^(a), —SR^(a), —OC(O)—R^(a),—N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —C(O)N(R^(a))₂,—N(R^(a))C(O)OR^(a), —OC(O)—N(R^(a))₂, —N(R^(a))C(O)R^(a),—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)R^(a) (where t is 1 or 2) and —S(O)_(t)N(R^(a))₂(where t is 1 or 2) where each R^(a) is independently hydrogen, alkyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), aryl (optionally substituted with halogen, hydroxy,methoxy, or trifluoromethyl), aralkyl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl),heterocyclylalkyl (optionally substituted with halogen, hydroxy,methoxy, or trifluoromethyl) heteroaryl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl).

“Alkynylene” or “alkynylene chain” refers to a straight or brancheddivalent hydrocarbon chain linking the rest of the molecule to a radicalgroup, consisting solely of carbon and hydrogen, containing at least onecarbon-carbon triple bond, and having from two to twelve carbon atoms.The alkynylene chain is attached to the rest of the molecule through asingle bond and to the radical group through a single bond. In certainembodiment, an alkynylene comprises two to eight carbon atoms (e.g.,C₂-C₈ alkynylene). In other embodiments, an alkynylene comprises two tofive carbon atoms (e.g., C₂-C₅ alkynylene). In other embodiments, analkynylene comprises two to four carbon atoms (e.g., C₂-C₄ alkynylene).In other embodiments, an alkynylene comprises two to three carbon atoms(e.g., C₂-C₃ alkynylene). In other embodiments, an alkynylene comprisestwo carbon atom (e.g., C₂ alkylene). In other embodiments, an alkynylenecomprises five to eight carbon atoms (e.g., C₅-C₈ alkynylene). In otherembodiments, an alkynylene comprises three to five carbon atoms (e.g.,C₃-C₅ alkynylene). Unless stated otherwise specifically in thespecification, an alkynylene chain is optionally substituted by one ormore of the following substituents: halo, cyano, nitro, oxo, thioxo,imino, oximo, trimethylsilanyl, —OR^(a), —SR^(a), —OC(O)—R^(a),—N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —C(O)N(R^(a))₂,—N(R^(a))C(O)OR^(a), —OC(O)—N(R^(a)), —N(R^(a))C(O)R^(a),—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)R^(a) (where t is 1 or 2) and —S(O)_(t)N(R^(a))₂(where t is 1 or 2) where each R^(a) is independently hydrogen, alkyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoremethyl), aryl (optionally substituted with halogen, hydroxy,methoxy, or trifluoromethyl), aralkyl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoremethyl),heterocyclylalkyl (optionally substituted with halogen, hydroxy,methoxy, or trifluoromethyl), heteroaryl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl).

“Aryl” refers to a radical derived from an aromatic monocyclic ormulticyclic hydrocarbon ring system by removing a hydrogen atom from aring carbon atom. The aromatic monocyclic or multicyclic hydrocarbonring system contains only hydrogen and carbon from five to eighteencarbon atoms, where at least one of the rings in the ring system isfully unsaturated, i.e., it contains a cyclic, delocalized (4n+2)π-electron system in accordance with the Hückel theory. The ring systemfrom which aryl groups are derived include, but are not limited to,groups such as benzene, fluorene, indane, indene, tetralin andnaphthalene. Unless stated otherwise specifically in the specification,the term “aryl” or the prefix “ar-” (such as in “aralkyl”) is meant toinclude aryl radicals optionally substituted by one or more substituentsindependently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl,cyano, nitro, optionally substituted aryl, optionally substitutedaralkyl, optionally substituted aralkenyl, optionally substitutedaralkynyl, optionally substituted carbocyclyl, optionally substitutedcarbocyclylalkyl, optionally substituted heterocyclyl, optionallysubstituted heterocyclylalkyl, optionally substituted heteroaryl,optionally substituted heteroarylalkyl, —R^(b)—OR^(a),—R^(b)—OC(O)—R^(a), —R^(b)—OC(O)—OR^(a), —R^(b)—OC(O)—N(R^(a))₂,—R^(b)—N(R^(a))₂, —R^(b)C(O) R^(a), —R^(b)—C(O)OR^(a),—R^(b)—C(O)N(R^(a))₂, —R^(b)O—R^(c)—C(O)N(R^(a))₂,—R^(b)—N(R^(a))C(O)OR^(a), —R^(b)—N(R^(a))C(O)R^(a),—R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)R^(a)(where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a) (where t is 1 or 2) and—R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2), where each R^(a) isindependently hydrogen, alkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), cycloalkylalkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl),heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), heterocyclylalkyl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl), orheteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy,or trifluoromethyl), each R^(b) is independently a direct bond or astraight or branched alkylene or alkenylene chain, and R^(c) is astraight or branched alkylene or alkenylene chain, and where each of theabove substituents is unsubstituted unless otherwise indicated.

“Aralkyl” refers to a radical of the formula —R^(c)-aryl where R^(c) isan alkylene chain as defined above, for example, methylene, ethylene,and the like. The alkylene chain part of the aralkyl radical isoptionally substituted as described above for an alkylene chain. Thearyl part of the aralkyl radical is optionally substituted as describedabove for an aryl group.

“Aralkenyl” refers to a radical of the formula —R^(d)-aryl where R^(d)is an alkenylene chain as defined above. The aryl part of the aralkenylradical is optionally substituted as described above for an aryl group.The alkenylene chain part of the aralkenyl radical is optionallysubstituted as defined above for an alkenylene group.

“Aralkynyl” refers to a radical of the formula —R^(e)-aryl, where R^(e)is an alkynylene chain as defined above. The aryl part of the aralkynylradical is optionally substituted as described above for an aryl group.The alkynylene chain part of the aralkynyl radical is optionallysubstituted as defined above for an alkynylene chain.

“Aralkoxy” refers to a radical bonded through an oxygen atom of theformula —O—R^(c)-aryl where R^(c) is an alkylene chain as defined above,for example, methylene, ethylene, and the like. The alkylene chain partof the aralkyl radical is optionally substituted as described above foran alkylene chain. The aryl part of the aralkyl radical is optionallysubstituted as described above for an aryl group.

“Carbocyclyl” refers to a stable non-aromatic monocyclic or polycyclichydrocarbon radical consisting solely of carbon and hydrogen atoms,which includes fused or bridged ring systems, having from three tofifteen carbon atoms. In certain embodiments, a carbocyclyl comprisesthree to ten carbon atoms. In other embodiments, a carbocyclyl comprisesfive to seven carbon atoms. The carbocyclyl is attached to the rest ofthe molecule by a single bond. Carbocyclyl is saturated (i.e.,containing single C—C bonds only) or unsaturated (i.e., containing oneor more double bonds or triple bonds). A fully saturated carbocyclylradical is also referred to as “cycloalkyl.” Examples of monocycliccycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, and cyclooctyl. An unsaturated carbocyclyl isalso referred to as “cycloalkenyl.” Examples of monocyclic cycloalkenylsinclude, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, andcyclooctenyl. Polycyclic carbocyclyl radicals include, for example,adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl,decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unlessotherwise stated specifically in the specification, the term“carbocyclyl” is meant to include carbocyclyl radicals that areoptionally substituted by one or more substituents independentlyselected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo,cyano, nitro, optionally substituted aryl, optionally substitutedaralkyl, optionally substituted aralkenyl, optionally substitutedaralkynyl, optionally substituted carbocyclyl, optionally substitutedcarbocyclylalkyl, optionally substituted heterocyclyl, optionallysubstituted heterocyclylalkyl, optionally substituted heteroaryl,optionally substituted heteroarylalkyl, —R^(b)—OR^(a),—R^(b)—OC(O)—R^(a), —R^(b)—OC(O)—OR^(a), —R^(b)—OC(O)—N(R^(a))₂,—R^(b)—N(R^(a))₂, —R^(b)—C(O) R^(a), —R^(b)—C(O)OR^(a),—R^(b)—C(O)N(R^(a))₂, —R^(b)—O—R^(c)—C(O)N(R^(a))₂,—R^(b)—N(R^(a))C(O)OR^(a), —R^(b)—N(R^(a))C(O)R^(a),—R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)R^(a)(where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a) (where t is 1 or 2) and—R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2), where each R isindependently hydrogen, alkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), cycloalkylalkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl),heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), heterocyclylalkyl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl), orheteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy,or trifluoromethyl), each R^(b) is independently a direct bond or astraight or branched alkylene or alkenylene chain, and R^(c) is astraight or branched alkylene or alkenylene chain, and where each of theabove substituents is unsubstituted unless otherwise indicated.

“Carbocyclylalkyl” refers to a radical of the formula —R^(c)-carbocyclylwhere R^(c) is an alkylene chain as defined above. The alkylene chainand the carbocyclyl radical is optionally substituted as defined above.

“Carbocyclylalkynyl” refers to a radical of the formula—R^(c)-carbocyclyl where R^(c) is an alkynylene chain as defined above.The alkynylene chain and the carbocyclyl radical is optionallysubstituted as defined above.

“Carbocyclylalkoxy” refers to a radical bonded through an oxygen atom ofthe formula —O—R^(c)-carbocyclyl where R^(c) is an alkylene chain asdefined above. The alkylene chain and the carbocyclyl radical isoptionally substituted as defined above.

As used herein, “carboxylic acid bioisostere” refers to a functionalgroup or moiety that exhibits similar physical, biological and/orchemical properties as a carboxylic acid moiety. Examples of carboxylicacid bioisosteres include, but are not limited to,

and the like.

“Deuteroalkyl” refers to an alkyl group where 1 or more hydrogen atomsof an alkyl are replaced with deuterium.

“Halo” or “halogen” refers to bromo, chloro, fluoro or iodosubstituents.

“Haloalkyl” refers to an alkyl radical, as defined above, that issubstituted by one or more halo radicals, as defined above, for example,trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl,1-fluoromethyl-2-fluoromethyl, trichloromethyl, dichloromethyl,chloromethyl, 2,2,2-trichloroethyl, 1-chloromethyl-2-chloroethyl,tribromomethyl, dibromomethyl, bromomethyl, 2,2,2-tribromoethyl,1-bromomethyl-2-bromoethyl, and the like. In some embodiments, the alkylpart of the haloalkyl radical is optionally substituted as defined abovefor an alkyl group.

“Fluoroalkyl” refers to an alkyl radical, as defined above, that issubstituted by one or more fluoro radicals, as defined above, forexample, trifluoromethyl, difluoromethyl, fluoromethyl,2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like. Insome embodiments, the alkyl part of the fluoroalkyl radical isoptionally substituted as defined above for an alkyl group.

“Heteroalkyl” refers to an alkyl group in which one or more skeletalatoms of the alkyl are selected from an atom other than carbon, e.g.,oxygen, nitrogen (e.g. —NH—, —N(alkyl)-), sulfur, or combinationsthereof. A heteroalkyl is attached to the rest of the molecule at acarbon atom of the heteroalkyl. In one aspect, a heteroalkyl is aC₁-C₆heteroalkyl. Unless stated otherwise specifically in thespecification, an heteroalkyl chain is optionally substituted by one ormore of the following substituents: halo, cyano, nitro, oxo, thioxo,imino, oximo, trimethylsilanyl, —OR^(a), —SR^(a), —OC(O)—R^(a),—N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —C(O)N(R^(a))₂,—N(R^(a))C(O)OR^(a), —OC(O)—N(R^(a))₂, —N(R^(a))C(O)R^(a),—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)R^(a) (where t is 1 or 2) and —S(O)_(t)N(R^(a))₂(where t is 1 or 2) where each R^(a) is independently hydrogen, alkyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), aryl (optionally substituted with halogen, hydroxy,methoxy, or trifluoromethyl), aralkyl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl),heterocyclylalkyl (optionally substituted with halogen, hydroxy,methoxy, or trifluoromethyl), heteroaryl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl).

“Heterocyclyl” refers to a stable 3- to 18-membered non-aromatic ringradical that comprises two to twelve carbon atoms and from one to sixheteroatoms selected from nitrogen, oxygen and sulfur. Unless statedotherwise specifically in the specification, the heterocyclyl radical isa monocyclic, bicyclic, tricyclic or tetracyclic ring system, whichoptionally includes fused or bridged ring systems. The heteroatoms inthe heterocyclyl radical are optionally oxidized. One or more nitrogenatoms, if present, are optionally quaternized. The heterocyclyl radicalis partially or fully saturated. The heterocyclyl is attached to therest of the molecule through any atom of the ring(s). Examples of suchheterocyclyl radicals include, but are not limited to, dioxolanyl,thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl,imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl,octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl,piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl,thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl,thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in thespecification, the term “heterocyclyl” is meant to include heterocyclylradicals as defined above that are optionally substituted by one or moresubstituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl,oxo, thioxo, cyano, nitro, optionally substituted aryl, optionallysubstituted aralkyl, optionally substituted aralkenyl, optionallysubstituted aralkynyl, optionally substituted carbocyclyl, optionallysubstituted carbocyclylalkyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, optionally substitutedheteroaryl, optionally substituted

heteroarylalkyl, —R^(b)—OR^(a), —R^(b)OC(O)—R^(a), —R^(b)—OC(O)—OR^(a),—R^(b)—OC(O)—N(R^(a))₂, —R^(b)—N(R^(a))₂, —R^(b)—C(O) R^(a),—R^(b)—C(O)OR^(a), —R^(b)—C(O)N(R^(a))₂, —R^(b)—O—R^(c)—C(O)N(R^(a))₂,—R^(b)—N(R^(a))C(O)OR^(a), —R^(b)—N(R^(a))C(O)R^(a),—R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)S(O)_(t)R^(a)(where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a) (where t is 1 or 2) and—R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2), where each R isindependently hydrogen, alkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), cycloalkylalkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl),heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), heterocyclylalkyl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl), orheteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy,or trifluoromethyl), each R^(b) is independently a direct bond or astraight or branched alkylene or alkenylene chain, and R^(c) is astraight or branched alkylene or alkenylene chain, and where each of theabove substituents is unsubstituted unless otherwise indicated.

“N-heterocyclyl” or “N-attached heterocyclyl” refers to a heterocyclylradical as defined above containing at least one nitrogen and where thepoint of attachment of the heterocyclyl radical to the rest of themolecule is through a nitrogen atom in the heterocyclyl radical. AnN-heterocyclyl radical is optionally substituted as described above forheterocyclyl radicals. Examples of such N-heterocyclyl radicals include,but are not limited to, 1-morpholinyl, 1-piperidinyl, 1-piperazinyl,1-pyrrolidinyl, pyrazolidinyl, imidazolinyl, and imidazolidinyl.

“C-heterocyclyl” or “C-attached heterocyclyl” refers to a heterocyclylradical as defined above containing at least one heteroatom and wherethe point of attachment of the heterocyclyl radical to the rest of themolecule is through a carbon atom in the heterocyclyl radical. AC-heterocyclyl radical is optionally substituted as described above forheterocyclyl radicals. Examples of such C-heterocyclyl radicals include,but are not limited to, 2-morpholinyl, 2- or 3- or 4-piperidinyl,2-piperazinyl, 2- or 3-pyrrolidinyl, and the like.

“Heterocyclylalkyl” refers to a radical of the formula—R^(c)-heterocyclyl where R^(c) is an alkylene chain as defined above.If the heterocyclyl is a nitrogen-containing heterocyclyl, theheterocyclyl is optionally attached to the alkyl radical at the nitrogenatom. The alkylene chain of the heterocyclylalkyl radical is optionallysubstituted as defined above for an alkylene chain. The heterocyclylpart of the heterocyclylalkyl radical is optionally substituted asdefined above for a heterocyclyl group.

“Heterocyclylalkoxy” refers to a radical bonded through an oxygen atomof the formula —O—R^(c)-heterocyclyl where R^(c) is an alkylene chain asdefined above. If the heterocyclyl is a nitrogen-containingheterocyclyl, the heterocyclyl is optionally attached to the alkylradical at the nitrogen atom. The alkylene chain of theheterocyclylalkoxy radical is optionally substituted as defined abovefor an alkylene chain. The heterocyclyl part of the heterocyclylalkoxyradical is optionally substituted as defined above for a heterocyclylgroup.

“Heteroaryl” refers to a radical derived from a 3- to 18-memberedaromatic ring radical that comprises two to seventeen carbon atoms andfrom one to six heteroatoms selected from nitrogen, oxygen and sulfur.As used herein, the heteroaryl radical is a monocyclic, bicyclic,tricyclic or tetracyclic ring system, wherein at least one of the ringsin the ring system is fully unsaturated, i.e., it contains a cyclic,delocalized (4n+2) π-electron system in accordance with the Hückeltheory. Heteroaryl includes fused or bridged ring systems. Theheteroatom(s) in the heteroaryl radical is optionally oxidized. One ormore nitrogen atoms, if present, are optionally quaternized. Theheteroaryl is attached to the rest of the molecule through any atom ofthe ring(s). Examples of heteroaryls include, but are not limited to,azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl,benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl,benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl,benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl,benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl(benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl,benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl,cyclopenta[d]pyrimidinyl,6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl,5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl,6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl,dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl,indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl,isoquinolyl, indolizinyl, isoxazolyl,5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl,1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl,5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl,phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl,purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl,pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl,pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl,quinolinyl, isoquinolinyl, tetrahydroquinolinyl,5,6,7,8-tetrahydroquinazolinyl,5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl,6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl,5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl,triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl,thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pyridinyl, and thiophenyl (i.e.thienyl). Unless stated otherwise specifically in the specification, theterm “heteroaryl” is meant to include heteroaryl radicals as definedabove which are optionally substituted by one or more substituentsselected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, haloalkenyl,haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl,optionally substituted aralkyl, optionally substituted aralkenyl,optionally substituted aralkynyl, optionally substituted carbocyclyl,optionally substituted carbocyclylalkyl, optionally substitutedheterocyclyl, optionally substituted heterocyclylalkyl, optionallysubstituted heteroaryl, optionally substituted

heteroarylalkyl, —R^(b)—OR^(a), —R^(b)—OC(O)—R^(a), —R^(b)—OC(O)—OR^(a),—R^(b)—OC(O)—N(R^(a))₂, —R^(b)—N(R^(a))₂, —R^(b)—C(O) R^(a),—R^(b)—C(O)OR^(a), —R^(b)—C(O)N(R^(a))₂, —R^(b)—O—R^(c)—C(O)N(R^(a))₂,—R^(b)—N(R^(a))C(O)OR^(a), —R^(b)—N(R^(a))C(O)R^(a),—R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)R^(a)(where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a) (where t is 1 or 2) and—R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2), where each R^(a) isindependently hydrogen, alkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), cycloalkylalkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl),heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), heterocyclylalkyl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl), orheteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy,or trifluoromethyl), each R^(b) is independently a direct bond or astraight or branched alkylene or alkenylene chain, and R^(c) is astraight or branched alkylene or alkenylene chain, and where each of theabove substituents is unsubstituted unless otherwise indicated.

“N-heteroaryl” refers to a heteroaryl radical as defined abovecontaining at least one nitrogen and where the point of attachment ofthe heteroaryl radical to the rest of the molecule is through a nitrogenatom in the heteroaryl radical. An N-heteroaryl radical is optionallysubstituted as described above for heteroaryl radicals.

“C-heteroaryl” refers to a heteroaryl radical as defined above and wherethe point of attachment of the heteroaryl radical to the rest of themolecule is through a carbon atom in the heteroaryl radical. AC-heteroaryl radical is optionally substituted as described above forheteroaryl radicals.

“Heteroarylalkyl” refers to a radical of the formula —R^(c)-heteroaryl,where R^(c) is an alkylene chain as defined above. If the heteroaryl isa nitrogen-containing heteroaryl, the heteroaryl is optionally attachedto the alkyl radical at the nitrogen atom. The alkylene chain of theheteroarylalkyl radical is optionally substituted as defined above foran alkylene chain. The heteroaryl part of the heteroarylalkyl radical isoptionally substituted as defined above for a heteroaryl group.

“Heteroarylalkoxy” refers to a radical bonded through an oxygen atom ofthe formula —O—R^(c)-heteroaryl, where R^(c) is an alkylene chain asdefined above. If the heteroaryl is a nitrogen-containing heteroaryl,the heteroaryl is optionally attached to the alkyl radical at thenitrogen atom. The alkylene chain of the heteroarylalkoxy radical isoptionally substituted as defined above for an alkylene chain. Theheteroaryl part of the heteroarylalkoxy radical is optionallysubstituted as defined above for a heteroaryl group.

The compounds disclosed herein, in some embodiments, contain one or moreasymmetric centers and thus give rise to enantiomers, diastereomers, andother stereoisomeric forms that are defined, in terms of absolutestereochemistry, as (R)— or (S)—. Unless stated otherwise, it isintended that all stereoisomeric forms of the compounds disclosed hereinare contemplated by this disclosure. When the compounds described hereincontain alkene double bonds, and unless specified otherwise, it isintended that this disclosure includes both E and Z geometric isomers(e.g., cis or trans.) Likewise, all possible isomers, as well as theirracemic and optically pure forms, and all tautomeric forms are alsointended to be included. The term “geometric isomer” refers to E or Zgeometric isomers (e.g., cis or trans) of an alkene double bond. Theterm “positional isomer” refers to structural isomers around a centralring, such as ortho-, meta-, and para-isomers around a benzene ring.

The compounds described herein may exhibit their natural isotopicabundance, or one or more of the atoms may be artificially enriched in aparticular isotope having the same atomic number, but an atomic mam ormass number different from the atomic mass or mass number predominantlyfound in nature. All isotopic variations of the compounds of the presentinvention, whether radioactive or not, are encompassed within the scopeof the present invention. For example, hydrogen has three naturallyoccurring isotopes, denoted ¹H (protium), ²H (deuterium), and ³H(tritium). Protium is the most abundant isotope of hydrogen in nature.Enriching for deuterium may afford certain therapeutic advantages, suchas increased in view half-life and/or exposure, or may provide acompound useful for investigating in vivo routes of drug elimination andmetabolism. Isotopically-enriched compounds may be prepared byconventional techniques well known to those skilled in the art or byprocesses analogous to those described in the Schemes and Examplesherein using appropriate isotopically-enriched reagents and/orintermediates. In some embodiments, the compounds described hereincontain one or more isotopic variants (e.g., deuterium, tritium, ¹³C,and/or ¹⁴C).

A “tautomer” refers to a molecule wherein a proton shift from one atomof a molecule to another atom of the same molecule is possible. Thecompounds presented herein, in certain embodiments, exist as tautomers.In circumstances where tautomerization is possible, a chemicalequilibrium of the tautomers will exist. The exact ratio of thetautomers depends on several factors, including physical state,temperature, solvent, and pH. Some examples of tautomeric equilibriuminclude:

“Pharmaceutically acceptable salt” includes both acid and base additionsalts. A pharmaceutically acceptable salt of any one of the substitutedsteroidal derivative compounds described herein is intended to encompassany and all pharmaceutically suitable salt forms. Preferredpharmaceutically acceptable salts of the compounds described herein arepharmaceutically acceptable acid addition salts and pharmaceuticallyacceptable base addition salts.

“Pharmaceutically acceptable acid addition salt” refers to those saltswhich retain the biological effectiveness and properties of the freebases, which are not biologically or otherwise undesirable, and whichare formed with inorganic acids such as hydrochloric acid, hydrobromicacid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid,hydrofluoric add, phosphorus acid, and the like. Also included are saltsthat are formed with organic acids such as aliphatic mono- anddicarboxylic acids, phenyl-substituted alkanoic acids, hyroxy alkanoicacid, alkanedioic acids, aromatic acids, aliphatic and, aromaticsulfonic acids, etc. and include, for example, acetic acid,trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid,oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,salicylic acid, and the like. Exemplary salts thus include sulfates,pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates,monohydrogenphosphates, dihydrogenphosphates, metaphosphates,pyrophosphates, chlorides, bromides, iodides, acetates,trifluoroacetates, propionates, caprylates, isobutyrates, oxalates,malonates, succinate suberates, sebacates, fumarates, maleates,mandelates, benzoates, chlorobenzoates, methylbenzoates,dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates,phenylacetates, citrates, lactates, malates, tartrates,methanesulfonates, and the like. Also contemplated are salts of aminoacids, such as arginates, gluconates, and galacturonates (see, forexample, Berge S. M. et al., “Pharmaceutical Salts,” Journal ofPharmaceutical Science, 66:1-19 (1997)). Acid addition salts of basiccompounds are, in some embodiments, prepared by contacting the free baseforms with a sufficient amount of the desired acid to produce the saltaccording to methods and techniques with which a skilled artisan isfamiliar.

“Pharmaceutically acceptable base addition salt” refers to those saltsthat retain the biological effectiveness and properties of the freeacids, which are not biologically or otherwise undesirable. These saltsare prepared from addition of an inorganic base or an organic base tothe free acid. Pharmaceutically acceptable base addition salts are, insome embodiments, formed with metals or amines, such as alkali andalkaline earth metals or organic amines. Salts derived from inorganicbases include, but are not limited to, sodium, potassium, lithium,ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminumsalts and the like. Salts derived from organic bases include, but arenot limited to, salts of primary, secondary, and tertiary amines,substituted amines including naturally occurring substituted amines,cyclic amines and basic ion exchange mains, for example, isopropylamine,trimethylamine, diethylamine, triethylamine, tripropylamine,ethanolamine, diethanolamine, 2-dimethylaminoethanol,2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine,caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine,hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline,N-methylglucamine, glucosamine, methylglucamine, theobromine, purines,piperazine, piperidine, N-ethylpiperidine, polyamine resins and thelike. See Berge et al., supra.

As used herein, “treatment” or “treating,” or “palliating” or“ameliorating” are used interchangeably. These terms refer to anapproach for obtaining beneficial or desired results including but notlimited to therapeutic benefit and/or a prophylactic benefit. By“therapeutic benefit” is meant eradication or amelioration of theunderlying disorder being treated. Also, a therapeutic benefit isachieved with the eradication or amelioration of one or more of thephysiological symptoms associated with the underlying disorder such thatan improvement is observed in the patient, notwithstanding that thepatient is still afflicted with the underlying disorder. Forprophylactic benefit, the compositions are, in some embodiments,administered to a patient at risk of developing a particular disease, orto a patient reporting one or more of the physiological symptoms of adisease, even though a diagnosis of this disease has not been made.

“Prodrug” is meant to indicate a compound that is, in some embodiments,converted under physiological conditions or by solvolysis to abiologically active compound described herein. Thus, the term “prodrug”refers to a precursor of a biologically active compound that ispharmaceutically acceptable. A prodrug is typically inactive whenadministered to a subject, but is converted in vivo to an activecompound, for example, by hydrolysis. The prodrug compound often offersadvantages of solubility, tissue compatibility or delayed release in amammalian organism (see, e.g., Bundgard, H., Design of Prodrugs (1985),pp. 7-9, 21-24 (Elsevier, Amsterdam).

Abbreviations used herein have their conventional meaning within thechemical and biological arts. The following abbreviations have theindicated meaning throughout Na₂HPO₄=disodium phosphate, AcOH=aceticacid, aq.=aqueous, NH₄Cl=ammonium chloride, DCM=dichloromethane,DMPU=1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone,ESI=electrospray ionization, EtOAc=ethyl acetate, g=gram, h=hour,LCMS=liquid chromatography mass spectrometry, LDA=lithiumdiisopropylamide, MgSO₄=magnesium sulfate, m/s=mass-to-charge ratio,mg=milligram, MeOH=methanol, min=minute, NMR=nuclear magnetic resonance,RT or rt=room temperature, sat.=saturated, NaHCO₃=sodium bicarbonate,NaBH₄=sodium borohydride, Na₂CO₃=sodium carbonate, NaCl=sodium chloride,Na₂SO₄=sodium sulfate, Na₂S₂O₃=sodium thiosulfate, TFA=trifluoroaceticacid, and THF=tetrahydrofuran.

Substituted Steroidal Derivative Compounds

Substituted steroidal derivative compounds are described herein that areGR inhibitors. These compounds, and compositions comprising thesecompounds, are useful for the treatment of cancer, neoplastic disease,and hypercortisolism diseases and disorders.

Some embodiments provided herein describe a compound having thestructure of Formula (I), or a pharmaceutically acceptable salt,solvate, or prodrug thereof:

wherein

-   ring A is a heteroaryl, aryl, cycloalkyl, or heterocyclyl;-   R¹ is —H, —NR⁴R⁵, optionally substituted alkylNR⁴R⁵, halo, —OR⁶,    —OH, optionally substituted alkyl, haloalkyl, optionally substituted    carbocyclyl, optionally substituted carbocyclylalkyl, optionally    substituted heteroalkyl, optionally substituted heterocyclyl,    optionally substituted heterocyclylalkyl, optionally substituted    hydroxyalkyl, optionally substituted aryl, optionally substituted    heteroaryl, —C(O)OR⁶, —C(O)NR⁴R⁵, —OC(O)OR⁶, —OC(O)NR⁴R⁵,    —S(O)₂NR⁴R⁵, —S(O)₂R⁷, —S(O)R⁷, —SR⁷, —NR⁴S(O)₂NR⁴R⁵, —P(O)(OR⁶)₂,    —P(O)(R⁶)₂, —CN, —CO₂H, or —NO₂;-   each R² is independently —NR⁴R⁵, optionally substituted alkylNR⁴R⁵,    halo, —OR⁶, —OH, optionally substituted alkyl, haloalkyl, optionally    substituted carbocyclyl, optionally substituted carbocyclylalkyl,    optionally substituted heteroalkyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, optionally    substituted hydroxyalkyl, —C(O)⁶, —C(O)OR⁶, —C(O)NR⁴R⁵, —OC(O)OR⁶,    —OC(O)NR⁴R⁵, —S(O)₂NR⁴R⁵, —S(O)₂R⁷, —S(O)R⁷, —SR⁷, —NR⁴S(O)₂NR⁴R⁵,    —CN, —CO₂H, or —NO₂;-   R³ is optionally substituted alkyl, halo, haloalkyl, optionally    substituted carbocyclyl, optionally substituted carbocyclylalkyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heteroalkyl, optionally    substituted aryl, optionally substituted heteroaryl, —Si(R⁶)₃, —OR⁶,    or —S(O)₂R⁷;-   R⁴ and R⁵ are each independently —H, optionally substituted alkyl,    haloalkyl, optionally substituted carbocyclyl, optionally    substituted aryl, optionally substituted heterocyclyl, optionally    substituted heteroaryl, —S(O)₂R⁷, —C(O)N(R¹³)₂, —C(O)R⁶, or    —C(O)OR⁶;    -   or R⁴ and R⁵ attached to the same N atom are taken together with        the N atom to which they are attached to form a substituted or        unsubstituted heterocycle;-   each R⁶ is independently optionally substituted alkyl, haloalkyl,    optionally substituted carbocyclyl, optionally substituted aryl,    optionally substituted heterocyclyl, or optionally substituted    heteroaryl;-   R⁷ is optionally substituted alkyl, haloalkyl, optionally    substituted carbocyclyl, optionally substituted heteroalkyl,    optionally substituted aryl, optionally substituted aralkyl,    optionally substituted heterocyclyl, or optionally substituted    heteroaryl;-   R⁸ and R⁹ are each independently —H, optionally substituted alkyl,    haloalkyl, halo, optionally substituted carbocyclyl, optionally    substituted carbocyclylalkyl, optionally substituted heteroalkyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, —OH, —OR⁶, —NR⁴R⁵, —C(O)NR⁴R⁵, —CN, —S(O)₂R⁷,    —C(O)₂H, —C(O)R⁶, or —C(O)OR⁶;    -   or R⁸ and R⁹ are taken together with the atom to which they are        attached to form a substituted or unsubstituted ring containing        0-2 heteroatoms selected from the group consisting of —O—, —NH—,        —NR⁶—, —S—, and —S(O)₂—;-   R¹⁰ and R¹¹ are each independently —H, optionally substituted alkyl,    halo, haloalkyl, optionally substituted carbocyclyl, optionally    substituted carbocyclylalkyl, optionally substituted heteroalkyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, —OH, —S(O)₂R⁷, —C(O)₂H, —C(O)R⁶, or —C(O)OR⁶;    -   or R¹⁰ and R¹¹ are taken together with the atom to which they        are attached to form a substituted or unsubstituted ring        containing 0-2 heteroatoms selected from the group consisting of        —O—, —NH—, —NR⁶—, —S—, and —S(O)₂—;-   R¹² is hydrogen, optionally substituted alkyl, haloalkyl,    deuteroalkyl, hydroxy, halo, optionally substituted carbocyclyl,    optionally substituted carbocyclylalkyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, or    optionally substituted heteroalkyl;-   each R¹³ is independently H, optionally substituted alkyl,    haloalkyl, optionally substituted carbocyclyl, optionally    substituted heteroalkyl, optionally substituted aryl, optionally    substituted aralkyl, optionally substituted heterocyclyl, or    optionally substituted heteroaryl;-   and n is 0, 1, 2, 3, or 4.

In some embodiments,

-   ring A is a monocyclic or bicyclic heteroaryl, monocyclic or    bicyclic aryl, monocyclic cycloalkyl, or monocyclic heterocyclyl;-   R¹ is —H, —NR⁴R⁵, optionally substituted alkylNR⁴R⁵, halo, —OR⁶,    —OH, optionally substituted alkyl, haloalkyl, optionally substituted    carbocyclyl, optionally substituted heteroalkyl, optionally    substituted heterocyclyl, optionally substituted hydroxyalkyl,    —C(O)NR⁴R⁵, —S(O)₂NR⁴R⁵, —S(O)₂R⁷, —NR⁴S(O)₂NR⁴R⁵, —P(O)(OR⁶)₂, —CN,    or —CO₂H;-   each R² is independently —NR⁴R⁵, optionally substituted alkylNR⁴R⁵,    halo, —OR⁶, —OH, optionally substituted alkyl, haloalkyl, optionally    substituted carbocyclyl, optionally substituted heteroalkyl,    optionally substituted heterocyclyl, optionally substituted    hydroxyalkyl, —C(O)NR⁴R⁵, —S(O)₂NR⁴R⁵, —S(O)₂R⁷, —NR⁴S(O)₂NR⁴R⁵,    —CN, or —CO₂H;-   R³ is optionally substituted alkyl, halo, haloalkyl, deuteroalkyl,    optionally substituted carbocyclyl, optionally substituted    carbocyclylalkyl, optionally substituted heterocyclyl, optionally    substituted heterocyclylalkyl, optionally substituted heteroalkyl,    optionally substituted aryl, optionally substituted heteroaryl,    —Si(R⁶)₃, —OR⁶, or —S(O)₂R⁷;-   R⁴ and R⁵ are each independently —H, optionally substituted alkyl,    haloalkyl, optionally substituted carbocyclyl, optionally    substituted aryl, optionally substituted heterocyclyl, optionally    substituted heteroaryl, —S(O)₂R⁷, —C(O)N(R¹³)₂, —C(O)R⁶, or    —C(O)OR⁶;    -   or R⁴ and R⁵ attached to the same N atom are taken together with        the N atom to which they are attached to form a substituted or        unsubstituted 4-, 5-, or 6-membered heterocycle;-   R⁶ is optionally substituted alkyl, haloalkyl, optimally substituted    carbocyclyl, optionally substituted aryl, optionally substituted    heterocyclyl, or optimally substituted heteroaryl;-   R⁷ is optionally substituted alkyl, haloalkyl, optionally    substituted carbocyclyl, optionally substituted heteroalkyl,    optionally substituted aryl, optionally substituted aralkyl,    optionally substituted heterocyclyl, or optionally substituted    heteroaryl;-   R⁸ and R⁹ are each independently —H, optionally substituted alkyl,    haloalkyl, halo, optionally substituted carbocyclyl, optionally    substituted carbocyclylalkyl, optionally substituted heteroalkyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, —OH, —S(O)₂R⁷, —C(O)₂H, —C(O)R⁶, or —C(O)OR⁶;    -   or R⁸ and R⁹ are taken together with the atom to which they are        attached to form a substituted or unsubstituted 3-, 4-, 5-, or        6-membered ring containing 0 or 1 heteroatom selected from the        group consisting of —O—, —NH—, —NR⁶—, —S—, and —S(O)₂—;-   R¹⁰ and R¹¹ are each independently —H, optionally substituted alkyl,    halo, haloalkyl, optionally substituted carbocyclyl, optionally    substituted heteroalkyl, or —OH;    -   or R¹⁰ and R¹¹ are taken together with the atom to which they        are attached to form a substituted or unsubstituted 3-, 4-, 5-,        or 6-membered ring containing 0 or 1 heteroatom selected from        the group consisting of —O—, —NH—, —NR⁶—, —S—, and —S(O)₂—;-   R¹² is hydrogen, optionally substituted alkyl, haloalkyl, hydroxy,    halo, optionally substituted carbocyclyl, or optionally substituted    heteroalkyl;-   each R¹³ is independently H, optionally substituted alkyl,    haloalkyl, optionally substituted carbocyclyl, optionally    substituted heteroalkyl, optionally substituted aryl, optionally    substituted aralkyl, optionally substituted heterocyclyl, or    optionally substituted heteroaryl;-   and n is 0, 1, 2, 3, or 4.

In some embodiments,

-   ring A is aryl or bicyclic heteroaryl;-   R¹ is —NR⁴R⁵, halo, —OR⁶, C₁₋₆alkyl, C₁₋₆fluoroalkyl,    C₃₋₆carbocyclyl, C₃₋₆heterocyclyl, aryl, heteroaryl, —C(O)NR⁴R⁵,    —S(O)₂NR⁴R⁵, —S(O)₂R⁷, —NR⁴S(O)₂NR⁴R⁵, —P(O)(R⁶)₂, —P(O)(OR⁶)₂, or    —CN;-   each R² is independently —NR⁴R⁵, halo, —OR⁶, C₁₋₆alkyl,    C₁₋₆fluoroalkyl, C₃₋₆carbocyclyl, C₁₋₆heteroalkyl, C₃₋₆heterocyclyl,    or —CN;-   R³ is C₁₋₆ alkyl, C₁₋₆ fluoroalkyl, carbocyclyl, or    heterocyclylalkyl;-   R⁴ and R⁵ are each independently —H, C₁₋₆alkyl, C₁₋₆ fluoroalkyl,    C₃₋₆ carbocyclyl, C₁₋₆ carbocyclylalkyl, C₂₋₆ heterocyclyl, C₁₋₆    alkylC₃₋₆heterocyclyl, —S(O)₂R⁷, or —(O)N(R¹³);    -   or R⁴ and R⁵ attached to the same N atom are taken together with        the N atom to which they are attached to form a substituted or        unsubstituted 4-, 5-, or 6-membered heterocycle;-   R⁶ is alkyl;-   R⁷ is C₁₋₆alkyl, C₃₋₆carbocyclyl, or phenyl optionally substituted    with halo or alkyl;-   R⁸ and R⁹ are each independently —H, C₁₋₆alkyl, C₁₋₆fluoroalkyl,    halo, or C₃₋₆carbocyclyl;-   R¹⁰ and R¹¹ are each independently —H or C₁₋₆ alkyl;-   R¹² is hydrogen or C₁₋₆ alkyl;-   each R¹³ is independently hydrogen or C₁₋₆ alkyl;-   and n is 0, 1, 2, 3, or 4.

In some embodiments,

-   ring A is phenyl, 3-benzodioxyxlyl, or 1,4-benzodioxanyl;-   R¹ is —NR⁴R⁵, halo, —OR⁶, alkyl, or fluoroalkyl;-   each R² is independently —NR⁴R⁵, halo, alkyl, carbocyclyl, alkoxy,    or —CN;-   R³ is C₁₋₆ alkyl, C₁₋₆ fluoroalkyl, carbocyclyl, deuteroalkyl, or    heteroalkyl;-   R⁴ and R⁵ are each independently —H, C₁₋₆alkyl, heteroalkyl, or    —S(O)₂R⁷;    -   or R⁴ and R⁵ attached to the same N atom are taken together with        the N atom to which they are attached to form a substituted or        unsubstituted 4-, 5-, or 6-membered heterocycle;-   R⁶ is alkyl;-   R⁷ is C₁₋₆alkyl, C₃₋₆carbocyclyl, or phenyl optionally substituted    with halo or alkyl;-   R⁸ and R⁹ are each independently —H or C₁₋₆alkyl;-   R¹⁰ and R¹¹ are each independently —H;-   R¹² is hydrogen;-   each R¹³ is independently hydrogen or C₁₋₆ alkyl;-   and n is 0, 1, or 2.

In some embodiments,

-   ring A is phenyl;-   R¹ is —NR⁴R⁵, —OR⁶, alkyl, or fluoroalkyl;-   each R² is independently —NR⁴R⁵, halo, alkyl;-   R³ is C₁₋₆ alkyl, C₁₋₆ fluoroalkyl, carbocyclyl, deuteroalkyl, or    heteroalkyl;-   R⁴ and R⁵ are each independently —H, C₁₋₆alkyl, or heteroalkyl;    -   or R⁴ and R⁵ attached to the same N atom are taken together with        the N atom to which they are attached to form a substituted or        unsubstituted 4-, 5-, or 6-membered heterocycle;-   R⁶ is alkyl;-   R⁷ is C₁₋₆alkyl, C₃₋₆carbocyclyl, or phenyl optionally substituted    with halo or alkyl;-   R⁸ and R⁹ are each independently —H or C₁₋₆alkyl;-   R¹⁰ and R¹¹ are each independently —H;-   R¹² is hydrogen;-   each R¹³ is independently hydrogen or C₁₋₆ alkyl;-   and n is 0, 1, or 2.

In some embodiments,

-   ring A is 3-benzodioxyxlyl, or 1,4-benzodioxanyl;-   R¹ is —H;-   R³ is C₁₋₆ alkyl;-   R⁸ and R⁹ are each independently —H or C₁₋₆alkyl;-   R¹⁰ and R¹¹ are each independently —H;-   R¹² is hydrogen;-   each R¹³ is independently hydrogen or C₁₋₆ alkyl;-   and n is 0.

For any and all of the embodiments of Formula (I), substituents areselected from among a subset of the listed alternatives.

In some embodiments, ring A is monocyclic aryl, bicyclic aryl,monocyclic heteroaryl, or bicyclic heteroaryl. In some embodiments, ringA is monocyclic heteroaryl or monocyclic aryl. In some embodiments, ringA is bicyclic heteroaryl or bicyclic aryl. In some embodiments, ring Ais N-bound heteroaryl. In some embodiments, ring A is C-boundheteroaryl. In some embodiments, ring A is aryl.

In certain embodiments, ring A is phenyl, naphthyl, furanyl, pyrrolyl,oxazolyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl,isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl,pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, quinolinyl,isoquinolinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, indolyl,indazolyl, benzoxazolyl, benzisoxazolyl, benzofuranyl, benzothienyl,benzothiazolyl, benzimidazolyl, purinyl, cinnolinyl, phthalazinyl,pteridinyl, pyridopyrimidinyl, pyrazolopyrimidinyl, or azaindolyl. Insome embodiments, R¹ is furanyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl,oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl,pyridazinyl, or triazinyl. In some embodiments, ring A is pyrimidinyl,pyridinyl, pyrazinyl, triazinyl, or thiazolyl. In certain embodiments,ring A is C-bound imidazolyl. In certain embodiments, ring A is N-boundimidazolyl. In some embodiments, ring A is pyrimidinyl. In someembodiments, ring A is pyrimidinyl optionally substituted with alkyl oralkoxy. In some embodiments, ring A is pyrazinyl. In some embodiments,ring A is triazinyl. In some embodiments, ring A is thiazolyl.

In some embodiments, ring A is phenyl, pyridinyl, pyrimidinyl,pyrazinyl, or pyridazinyl. In some embodiments, ring A is phenyl.

In some embodiments, ring A is a bicyclic heteroaryl. In certainembodiments, ring A is an optionally substituted 3-benzodioxyxlyl or1,4-benzodioxanyl. In some embodiments, ring A is an unsubstituted3-benzodioxyxlyl or 1,4-benzodioxanyl. In some embodiments, ring A isphenyl, 3-benzodioxyxlyl, or 1,4-benzodioxanyl

In some embodiments, R¹ is —H, —NR⁴R⁵, optionally substitutedalkylNR⁴R⁵, halo, optionally substituted alkyl, fluoroalkyl, optionallysubstituted carbocyclyl, optionally substituted carbocyclylalkyl,optionally substituted heterocyclyl, optionally substitutedheterocyclylalkyl, optionally substituted hydroxyalkyl, optionallysubstituted aryl, optionally substituted heteroaryl, —C(O)NR⁴R⁵,—OC(O)OR⁶, —OC(O)NR⁴R⁵, —S(O)₂NR⁴R⁵, —S(O)₂R⁷, —S(O)R⁷, —SR⁷,—NR⁴S(O)₂NR⁴R⁵, —P(O)(OR⁶)₂, —P(O)(R⁶)₂, —CN, or —NO₂. In someembodiments, R¹ is —H, —NR⁴R⁵, halo, —OR⁶, optionally substituted alkyl,fluoroalkyl, optionally substituted carbocyclyl, optionally substitutedheterocyclyl, optionally substituted aryl, optionally substitutedheteroaryl, —C(O)NR⁴R⁵, —S(O)₂NR⁴R⁵, —S(O)₂R⁷, —NR⁴S(O)₂NR⁴R⁵,—P(O)(R⁶)₂, —P(O)(OR⁶)₂, or —CN. In some embodiments, R¹ is —H, —NR⁴R⁵,optionally substituted alkylNR⁴R⁵, halo, —OR⁶, optionally substitutedalkyl, fluoroalkyl, optionally substituted carbocyclyl, optionallysubstituted heteroalkyl, optionally substituted heterocyclyl, —C(O)R⁶,—C(O)NR⁴R⁵, —S(O)₂NR⁴R⁵, —S(O)₂R⁷, —NR⁴S(O)₂NR⁴R⁵, —CN, or —CO₂H. Insome embodiments, R¹ is —NR⁴R⁵, halo, —OR⁶, alkyl, fluoroalkyl,carbocyclyl, heteroalkyl, heterocyclyl, —S(O)₂NR⁴R⁵, —S(O)₂R⁷,—NR⁴S(O)₂NR⁴R⁵, or —CN. In some embodiments, R¹ is —NR⁴R⁵, halo, —OR⁶,C₁₋₆alkyl, C₁₋₆fluoroalkyl, C₃₋₆carbocyclyl, C₃₋₆heterocyclyl, aryl,heteroaryl, —C(O)NR⁴R⁵, —S(O)₂NR⁴R⁵, —S(O)₂R⁷, —NR⁴S(O)₂NR⁴R⁵,—P(O)(R⁶)₂, —P(O)(OR⁶)₂, or —CN. In some embodiments, R¹ is —NR⁴R⁵,halo, —OR⁶, —S(O)₂NR⁴R⁵, —P(O)(R⁶)₂, or —P(O)(OR⁶)₂. In certainembodiments, R¹ is —NR⁴R⁵, halo, —OR⁶, alkyl, or fluoroalkyl. In certainembodiments, R¹ is halo, —OR⁶, or alkyl. In other embodiments, R¹ is—NMe₂, —NHMe, —NH₂, —NEt₂, —NHEt, —NPr₂, —NHPr, —N(i-Pr₂), —NH(i-Pr),—NBu₂, —NHBu, —NEt₂, —NHEt, —N(i-Bu₂), —NH(i-Bu), —NMeEt, —NMePr,—N(Me)(i-Pr), —NMePr, —N(Me)(Bu), —NMeBu, —NEtPr, —N(Et)(i-Pr),—N(Et)(Bu), —NEtBu, methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl,sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, iso-propoxy,morpholino, or pyrrolidino. In certain embodiments, R¹ is C₁₋₆alkyl,fluoroalkyl, C₃₋₆carbocyclyl, or C₃₋₆heterocyclyl. In some embodiments,R¹ is —H. In some embodiments, R¹ is —NR⁴R⁵. In some embodiments, R¹ is—NMe₂. In some embodiments, R¹ is —NHMe. In some embodiments, R¹ is—NH₂. In some embodiments, R¹ is —NMeEt. In some embodiments, R¹ is—NEt₂. In some embodiments, R¹ is halo. In some embodiments, R¹ isfluoro. In some embodiments, R¹ is chloro. In some embodiments, R¹ isbromo. In some embodiments, R¹ is C₁₋₆alkyl. In some embodiments, R¹ ismethyl. In some embodiments, R¹ is ethyl. In some embodiments, R¹ ispropyl. In some embodiments, R¹ is iso-propyl. In some embodiments, R¹is carbocyclyl. In some embodiments, R¹ is cyclopropyl. In someembodiments, R¹ is cyclobutyl. In some embodiments, R¹ is cyclopentyl.In some embodiments, R¹ is cyclohexyl. In some embodiments, R¹ is —OR⁶.In some embodiments, R¹ is methoxy. In some embodiments, R¹ is ethoxy.In some embodiments, R¹ is propoxy. In some embodiments, R¹ isiso-propoxy. In some embodiments, R¹ is heterocyclyl. In someembodiments, R¹ is azetidino, morpholino, thiomorpholino, piperidino,piperazino, or pyrrolidino. In some embodiments, R¹ is morpholino. Insome embodiments, R¹ is pyrrolidino. In some embodiments, R¹ isazetidino.

In other embodiments, R¹ is optionally substituted monocyclic aryl,optionally substituted bicyclic aryl, optionally substituted monocyclicheteroaryl, or optionally substituted bicyclic heteroaryl. In certainembodiments, R¹ is phenyl, naphthyl, furanyl, pyrrolyl, oxazolyl,thiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl,isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl,pyrazinyl, pyridazinyl, triazinyl, quinolinyl, isoquinolinyl,quinazolinyl, quinoxalinyl, naphthyridinyl, indolyl, indazolyl,benzoxazolyl, benzisoxazolyl, benzofuranyl, benzothienyl,benzothiazolyl, benzimidazolyl, purinyl, cinnolinyl, phthalazinyl,pteridinyl, pyridopyrimidinyl, pyrazolopyrimidinyl, or azaindolyl. Insome embodiments, R¹ is furanyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl,oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl,pyridazinyl, or triazinyl. In some embodiments, R¹ is pyrimidinyl,pyridinyl, pyrazinyl, triazinyl, or thiazolyl. In certain embodiments,R¹ is C-bound imidazolyl. In certain embodiments, R¹ is N-boundimidazolyl. In some embodiments, R¹ is pyrimidinyl. In some embodiments,R¹ is pyrimidinyl optionally substituted with alkyl or alkoxy. In someembodiments, R¹ is pyrazinyl. In some embodiments, R¹ is triazinyl. Insome embodiments, R¹ is thiazolyl.

In certain embodiments, R¹ is optionally substituted with halo, alkyl,hydroxy, alkoxy, or fluoroalkyl. In certain embodiments, R¹ isoptionally substituted with halo, alkyl, or alkoxy. In some embodiments,R¹ is optionally substituted with fluoro or C₁₋₆alkyl. In someembodiments, R¹ is optionally substituted with fluoro or methyl. In someembodiments, R¹ is optionally substituted with methyl or methoxy.

In some embodiments, each R² is independently —NR⁴R⁵, optionallysubstituted alkylNR⁴R⁵, halo, —OR⁶, —OH, optionally substituted alkyl,haloalkyl, optionally substituted carbocyclyl, optionally substitutedcarbocyclylalkyl, optionally substituted heteroalkyl, optionallysubstituted heterocyclyl, optionally substituted heterocyclylalkyl,optionally substituted hydroxyalkyl, —C(O)R⁶, —C(O)NR⁴R⁵, —S(O)₂NR⁴R⁵,—S(O)₂R⁷, —NR⁴S(O)₂NR⁴R⁵, or —CN. In some embodiments, each R² isindependently —NR⁴R⁵, alkylNR⁴R⁵, halo, —OR⁶, —OH, alkyl, haloalkyl,carbocyclyl, carbocyclylalkyl, heteroalkyl, heterocyclyl,heterocyclylalkyl, hydroxyalkyl, —C(O)R⁶, —C(O)NR⁴R⁵, —S(O)NR⁴R⁵,—S(O)₂R⁷, —NR⁴S(O)₂NR⁴R⁵, or —CN. In some embodiments, —NR⁴R⁵, halo,—OR⁶, optionally substituted alkyl, fluoroalkyl, optionally substitutedcarbocyclyl, optionally substituted heteroalkyl, optionally substitutedheterocyclyl, —C(O)NR⁴R⁵, —S(O)₂NR⁴R⁵, —S(O)₂R⁷, —NR⁴S(O)₂NR⁴R⁵, —CN, or—CO₂H. In certain embodiments, each R² is independently —NR⁴R⁵, halo,—OR⁶, —OH, optionally substituted alkyl, fluoroalkyl, optionallysubstituted carbocyclyl, optionally substituted heteroalkyl, optionallysubstituted heterocyclyl, optionally substituted hydroxyalkyl,—S(O)₂NR⁴R⁵, —S(O)₂R⁷, —NR⁴S(O)₂NR⁴R⁵, or —CN. In some embodiments, eachR² is independently —NR⁴R⁵, halo, —OR⁶, alkyl, fluoroalkyl, carbocyclyl,heteroalkyl, heterocyclyl, —S(O)₂NR⁴R⁵, —NR⁴S(O)₂NR⁴R⁵, or —S(O)₂R⁷. Insome embodiments, each R² is independently —NR⁴R⁵, C₁₋₆alkylNR⁴R⁵, halo,—OR⁶, —OH, C₁₋₆alkyl, C₁₋₆fluoroalkyl, C₃₋₆carbocyclyl,C₁₋₆alkylC₃₋₆carbocyclyl, C₁₋₆heteroalkyl, C₃₋₆heterocyclyl,C₁₋₆alkylC₃₋₆heterocyclyl, C₁₋₆hydroxyalkyl, or —CN. In someembodiments, each R² is independently —C(O)R⁵, —(O)NR⁴R⁵, —S(O)₂NR⁴R⁵,—S(O)₂R⁷, or —CN. In some embodiments, each R² is independently —NR⁴R⁵,halo, —OR⁶, C₁₋₆alkyl, C₁₋₆fluoroalkyl, C₃₋₆carbocyclyl,C₁₋₆heteroalkyl, C₃₋₆heterocyclyl, or —CN. In some embodiments, each R²is independently —NR⁴R⁵, halo, alkyl, carbocyclyl, alkoxy, or —CN. Insome embodiments, each R² is independently —NR⁴R⁵, halo, alkyl, oralkoxy. In some embodiments, each R² is independently methyl, methoxy,ethyl, propyl, iso-propyl, cyclopropyl, fluoro, chloro, or —NMe₂. Insome embodiments, each R² is —NMe₂, —NHMe, —NH₂, —NEt₂, —NHEt, —NPr₂,—NHPr, —N(i-Pr₂), —NH(i-Pr), —NBu₂, —NHBu, —NEt₂, —NHEt, —N(i-Bu₂),—NH(i-Bu), —NMeEt, —NMePr, —N(Me)(i-Pr), —NMePr, —N(Me)(Bu), —NMeBu,—NEtPr, —N(Et)(i-Pr), —N(Et)(Bu), —NEtBu, methyl, ethyl, propyl,iso-propyl, butyl, iso-butyl, sec-butyl, tert-butyl, methoxy, ethoxy,propoxy, iso-propoxy, morpholino, or pyrrolidino. In some embodiments,each R² is independently methyl, methoxy, iso-propyl, cyclopropyl,fluoro, chloro, or —NMe₂. In some embodiments, R² is methoxy. In someembodiments, R² is methyl. In some embodiments R² is ethyl. In someembodiments, R² is iso-propyl. In some embodiments, R² is propyl. Insome embodiments, R² is cyclopropyl. In some embodiments, R² iscyclobutyl. In some embodiments, R² is fluoro. In some embodiments, R²is chloro. In some embodiments, R² is —NMe₂. In some embodiments, R² is—NH₂. In some embodiments, R² is —NHMe. In some embodiments, R² is—NMeEt.

In certain embodiments, each R² is independently optionally substitutedwith halo, alkyl, hydroxy, alkoxy, or fluoroalkyl. In some embodiments,each R² is independently optionally substituted with fluoro orC₁₋₆alkyl. In some embodiments, each R² is independently optionallysubstituted with fluoro or methyl.

In some embodiments, R³ is alkyl, halo, haloalkyl, deuteroalkyl,carbocyclyl, carbocyclylalkyl, heterocyclyl, heterocyclylalkyl, aryl,heteroaryl, —Si(R⁶)₃, —OR⁶, or —S(O)₂R⁷. In some embodiments, R³ isalkyl, halo, haloalkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl,heterocyclylalkyl, or heteroalkyl. In some embodiments, R³ is optionallysubstituted C₁₋₁₀alkyl, halo, haloalkyl, deuteroalkyl, carbocyclyl,optionally substituted aryl, or optionally substituted heteroaryl,wherein R³ is optionally substituted with halo, alkyl, alkoxy, hydroxy,—NR⁴R⁵, or —S(O)₂R⁷. In some embodiments, R³ is C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ deuteroalkyl, C₃₋₆ carbocyclyl, C₃₋₆ carbocyclylC₁₋₆alkyl, C₃₋₆heterocyclyl, C₃₋₆ heterocyclylC₁₋₆ alkyl. In someembodiments, R³ is alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl,heterocyclyl, heterocyclylalkyl, or heteroalkyl. In some embodiments, R³is C₁₋₆ alkyl, C₁₋₆ fluoroalkyl, carbocyclyl, or heterocyclylalkyl. Incertain embodiments, R³ is C₃₋₈ alkyl or C₁₋₆ fluoroalkyl. In someembodiments, R³ is C₁₋₆ alkyl. In some embodiments, R³ is C₁₋₈ alkyl. Insome embodiments, R³ is C₂₋₈ alkyl. In some embodiments, R³ is C₃₋₆alkyl. In some embodiments, R³ is methyl. In some embodiments, R³ isethyl. In some embodiments, R³ is propyl. In some embodiments, R³ isi-propyl. In some embodiments, R³ is t-butyl. In some embodiments, R³ isbutyl. In some embodiments, R³ is isobutyl. In some embodiments, R³ issec-butyl. In some embodiments, R³ is carbocyclyl. In some embodiments,R³ is cyclopropyl. In some embodiments, R³ is cyclobutyl. In someembodiments, R³ is cyclopentyl. In some embodiments, R³ is cyclohexyl.In some embodiments, R³ is halo. In some embodiments, R³ is fluoro. Insome embodiments, R³ is chloro. In some embodiments, R³ is bromo. Insome embodiments, R³ is trifluoromethyl. In some embodiments, R³ ishydroxyalkyl. In some embodiments, R³ is deuteromethyl. In someembodiments, R³ is —Si(R⁶)₃. In some embodiments, R³ is —Si(Me)₃. Insome embodiments, R³ is —Si(Ph)₃. In some embodiments, R³ is —OR⁶. Insome embodiments, R³ is —S(O)₂R⁷.

In other embodiments, R³ is optionally substituted aryl or optionallysubstituted heteroaryl. In certain specific embodiments, R³ is phenyl,furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl,triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl,thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, ortriazinyl. In some embodiment, R³ is phenyl optionally substituted withhalo, alkyl, alkoxy, hydroxy, —NR⁴R⁵, or —S(O)₂R⁷. In some embodiments,R³ is pyridinyl optionally substituted with halo, alkyl, alkoxy,hydroxy, —NR⁴R⁵, or —S(O)₂R⁷. In some embodiments, R³ is phenyl. In someembodiments, R³ is pyridinyl.

In certain embodiments, R³ is optionally substituted with halo, alkyl,hydroxy, alkoxy, —NR⁴R⁵, —S(O)₂R⁷ or fluoroalkyl. In some embodiments,R³ is optionally substituted with chloro, fluoro, methyl, ethyl, propyl,iso-propyl, butyl, iso-butyl, sec-butyl, tert-butyl, hydroxy, methoxy,ethoxy, propoxy, iso-propoxy, dimethylamino, diethylamino, methylamino,amino, —S(O)₂Me, or trifluoromethyl. In certain embodiments, R³ isoptionally substituted with chloro, fluoro, methyl, hydroxy, methoxy,dimethylamino, —S(O)Me, or trifluoromethyl.

In some embodiments, R⁴ and R⁵ are each independently —H, optionallysubstituted alkyl, fluoroalkyl, optionally substituted carbocyclyl,optionally substituted carbocyclylalkyl, optionally substitutedheterocyclyl, optionally substituted heterocyclylalkyl, —S(O)₂R⁷, or—C(O)N(R¹³)₂. In some embodiments, R⁴ and R⁵ are each independently —H,C₁₋₆ alkyl, C₁₋₆ fluoroalkyl, C₃₋₆ carbocyclyl, C₁₋₆ carbocyclylalkyl,C₂₋₆ heterocyclyl, C₁₋₆ alkylC₃₋₆heterocyclyl, —S(O)₂R⁷, or—C(O)N(R¹³)₂. In some embodiments, R⁴ and R⁵ are each independently —H,C₁₋₆alkyl, C₁₋₆fluoroalkyl, C₃₋₆carbocyclyl, C₃₋₅heterocyclyl, or—S(O)₂R⁷. In some embodiments, R⁴ and R₅ are each independently —H,C₁₋₆alkyl, or —S(O)₂R⁷. In some embodiments, R⁴ and R⁵ are eachindependently —H or alkyl. In some embodiments, R⁴ and R⁵ are eachindependently —H, methyl, ethyl, propyl, iso-propyl, butyl, sec-butyl,iso-butyl, tert-butyl, or —S(O)₂R⁷. In some embodiments, R⁴ and R⁵ areeach independently —H, methyl, ethyl, propyl, or iso-propyl. In someembodiments, R⁴ and R⁵ are —H. In some embodiments, R⁴ and R⁵ aremethyl. In some embodiments, R⁴ is methyl and R⁵ is ethyl. In someembodiments, R⁴ is methyl and R⁵ is propyl. In some embodiments, R⁴ ismethyl and R⁵ is iso-propyl. In some embodiments, R⁴ is H and R⁵ isiso-propyl. In some embodiments, R⁴ and R⁵ are each independently —H or—C(O)N(R¹³)₂.

In other embodiments, R⁴ and R⁵ attached to the same N atom are takentogether with the N atom to which they are attached to form asubstituted or unsubstituted 4-, 5-, or 6-membered ring heterocycleadditionally containing 0-3 heteroatoms selected from —O—, —NH—, —NR⁶—,—S—, and —S(O)₂—. In some embodiments, R⁴ and R⁵ attached to the same Natom are taken together with the N atom to which they are attached toform a 4-, 5- or 6-membered heterocycle additionally containing 0 or 1oxygen heteroatom. In other embodiments, R⁴ and R⁵ attached to the sameN atom are taken together with the N atom to which they are attached toform a substituted or unsubstituted 4-, 5-, or 6-membered ringheterocycle additionally containing 1 heteroatoms selected from —O—,—NH—, —NR⁶—, —S—, and —S(O)₂—. In other embodiments, R⁴ and R⁵ attachedto the same N atom are taken together with the N atom to which they areattached to form a 4-, 5-, or 6-membered ring heterocycle additionallycontaining 1 oxygen heteroatom. In other embodiments, R⁴ and R⁵ attachedto the same N atom are taken together with the N atom to which they areattached to form a 4-, 5-, or 6-membered ring. In some embodiments, the4-, 5-, or 6-membered ring is

In certain embodiments, R⁴ and R⁵ are each independently optionallysubstituted with halo, alkyl, hydroxy, alkoxy, or fluoroalkyl. In someembodiments, R⁴ and R⁵ are each independently optionally substitutedwith fluoro or C₁₋₆alkyl. In some embodiments, R⁴ and R⁵ are eachindependently optionally substituted with fluoro or methyl.

In some embodiments, R⁶ is optionally substituted alkyl, fluoroalkyl,optionally substituted aryl, optionally substituted carbocyclyl, oroptionally substituted heterocyclyl. In some embodiments, R⁶ isoptionally substituted alkyl, fluoroalkyl, optionally substitutedcarbocyclyl, or optionally substituted heterocyclyl. In someembodiments, R⁶ is alkyl, aryl, carbocyclyl, or heterocyclyl. In someembodiments, R⁶ is alkyl, carbocyclyl, or heterocyclyl. In someembodiments, R⁶ is alkyl, carbocyclyl, or fluoroalkyl. In someembodiments, R⁶ is C₁₋₆alkyl, C₁₋₆fluoroalkyl, C₃₋₆carbocyclyl, orC₃₋₆heterocyclyl. In certain embodiments, R⁶ is C₁₋₆alkyl. In certainembodiments, R⁶ is methyl, ethyl, propyl, iso-propyl, butyl, sec-butyl,iso-butyl, or tert-butyl. In some embodiments, R⁶ is optionallysubstituted phenyl.

In some embodiments, R⁷ is alkyl, carbocyclyl, optionally substitutedaryl, optionally substituted aralkyl, or optionally substitutedheterocyclyl. In some embodiments, R⁷ is C₁₋₆alkyl, C₃₋₆carbocyclyl, oraryl optionally substituted with halo or alkyl. In some embodiments, R⁷is C₁₋₆alkyl, C₃₋₆carbocyclyl, or phenyl optionally substituted withhalo or alkyl. In some embodiments, R⁷ is optionally substituted benzyl.In some embodiments, R⁷ is C₃₋₆carbocyclyl. In some embodiments, R⁷ isphenyl. In some embodiments, R⁷ is phenyl substituted with 1-4 C₁₋₆alkylor fluoro substituents. In some embodiments, R⁷ is phenyl substitutedwith a C₁₋₆alkyl or fluoro substituent. In some embodiments, R⁷ isalkyl, carbocyclyl, aralkyl, or heterocyclyl.

In certain embodiments, R⁷ is optionally substituted with halo, alkyl,hydroxy, alkoxy, or fluoroalkyl. In some embodiments, R⁷ is optionallysubstituted with fluoro or C₁₋₆alkyl. In some embodiments, R⁷ isoptionally substituted with fluoro or methyl.

In some embodiments, R⁸ and R⁹ are each independently —H, C₁₋₆alkyl,C₁₋₆haloalkyl, halo, C₃₋₆carbocyclyl, C₁₋₆alkylC₃₋₆carbocyclyl,C₁₋₆heteroalkyl, C₃₋₆heterocyclyl, C₁₋₆alkylC₃₋₆heterocyclyl, —OH, —OR⁶,—NR⁴R⁵, —C(O)NR⁴R⁵, —CN, —S(O)₂R⁷, —(O)₂H, —C(O)R⁶, or —C(O)OR⁶ or R⁸and R⁹ are taken together with the atom to which they are attached toform a ring containing 0-2 heteroatoms selected from the groupconsisting of —O—, —NH—, —NR⁶—, —S—, and —S(O)₂—. In some embodiments,R⁸ and R⁹ are each independently —H, C₁₋₆alkyl, halo, C₃₋₆carbocyclyl,methoxy, ethoxy, propoxy, iso-propoxy, —NH₂, —NMe₂, —NHMe, —NEt₂,—C(O)NH₂, —C(O)NMe₂, —C(O)NHMe, or —CN. In some embodiments, R⁸ and R⁹are each independently —H, C₁₋₆alkyl, C₁₋₆fluoroalkyl, halo, orC₃₋₆carbocyclyl. In some embodiments, R⁸ and R⁹ are each independently—H, C₁₋₆alkyl, or C₃₋₆carbocyclyl. In some embodiments, R⁸ and R⁹ areeach independently —H or C₁₋₆alkyl. In some embodiments, R⁸ is —H and R⁹is C₁₋₆alkyl, C₁₋₆fluoroalkyl, or C₃₋₆carbocyclyl. In some embodiments,R⁸ is —H and R⁹ is alkyl. In some embodiments, R⁸ is C₁₋₆alkyl,C₁₋₆fluoroalkyl, or C₃₋₆carbocyclyl and R⁹ is —H. In some embodiments,R⁸ is methyl and R⁹ is —H. In some embodiments, R⁸ and R⁹ are —H. Insome embodiments, R⁸ and R⁹ are C₁₋₆alkyl. In some embodiments, R⁸ andR⁹ are methyl.

In other embodiments, R⁸ and R⁹ are taken together with the atom towhich they are attached to form a 3-, 4-, 5-, or 6-membered ringcontaining 0-2 heteroatoms selected from the group consisting of —O—,—NH—, —NR⁶—, —S—, and —S(O)₂—. In some embodiments, R⁸ and R⁹ are takentogether with the atom to which they are attached to form a 3-, 4-, 5-,or 6-membered carbocyclic ring.

In some embodiments, R¹⁰ and R¹¹ are each independently —H, alkyl, halo,haloalkyl, carbocyclyl, heteroalkyl, or —OH. In other embodiments, R¹⁰and R¹¹ are each independently —H, C₁₋₆ alkyl, halo, C₁₋₆ alkoxy, or—OH. In certain embodiments, R¹⁰ and R¹¹ are each independently —H orC₁₋₆ alkyl. In certain embodiments, R¹⁰ and R¹¹ are each independently—H, fluoro, chloro, methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl,sec-butyl, or tert-butyl. In certain embodiments, R¹⁰ and R¹¹ are eachindependently —H, fluoro, or methyl. In certain embodiments, R¹⁰ and R¹¹are each independently —H or methyl. In certain embodiments, R¹⁰ and R¹¹are each independently —H or fluoro. In certain embodiments, R¹⁰ and R¹¹are both —H. In certain embodiments, R¹⁰ and R¹¹ are each independently—H or methoxy. In certain embodiments, R¹⁰ and R¹¹ are eachindependently —H or —OH. In certain embodiments, R¹⁰ and R¹¹ are eachindependently —H or fluoro. In certain embodiments, R¹⁰ and R¹¹ are eachindependently —H or chloro.

In some embodiments, R¹⁰ and R¹¹ are each independently —H, alkyl, halo,haloalkyl, carbocyclyl, heteroalkyl, or —OH, wherein at least one of R¹⁰or R¹¹ is not H. In other embodiments, R¹⁰ and R¹¹ are eachindependently —H, C₁₋₆ alkyl, halo, C₁₋₆ alkoxy, or —OH, wherein atleast one of R¹⁰ or R¹¹ is not H. In certain embodiments, R¹⁰ and R¹¹are each independently —H or C₁₋₆ alkyl, wherein at least one of R¹⁰ orR¹¹ is not H. In certain embodiments, R¹⁰ and R¹¹ are each independently—H, fluoro, chloro, methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl,sec-butyl, or tert-butyl, wherein at least one of R¹⁰ or R¹¹ is not H.In certain embodiments, R¹⁰ and R¹¹ are each independently —H, fluoro,or methyl, wherein at least one of R¹⁰ or R¹¹ is not H. In certainembodiments, R¹⁰ and R¹¹ are each independently —H or methyl, wherein atleast one of R¹⁰ or R¹¹ is not H. In certain embodiments, R¹⁰ and R¹¹are each independently —H or fluoro, wherein at least one of R¹⁰ or R¹¹is not H. In certain embodiments, R¹⁰ and R¹¹ are each independently —Hor methoxy, wherein at least one of R¹⁰ or R¹¹ is not H. In certainembodiments, R¹⁰ and R¹¹ are each independently —H or —OH, wherein atleast one of R¹⁰ or R¹¹ is not H. In certain embodiments, R¹⁰ and R¹¹are each independently —H or fluoro, wherein at least one of R¹⁰ or R¹¹is not H. In certain embodiments, R¹⁰ and R¹¹ are each independently —Hor chloro, wherein at least one of R¹⁰ or R¹¹ is not H.

In some embodiments, R¹⁰ and R¹¹ are methyl. In some embodiments, R¹⁰and R¹¹ are ethyl. In some embodiments, R¹⁰ and R¹¹ are propyl. In someembodiments, R¹⁰ and R¹¹ are fluoro. In some embodiments, R¹⁰ and R¹¹are chloro. In some embodiments, R¹⁰ and R¹¹ are bromo. In someembodiments, R¹⁰ and R¹¹ are methoxy. In some embodiments, R¹⁰ and R¹¹are ethoxy. In some embodiments, R¹⁰ and R¹¹ are —OH.

In some embodiments, R¹⁰ and R¹¹ are taken together with the atom towhich they are attached to form a 3-, 4-, 5-, or 6-membered ring. Insome embodiments, R¹⁰ and R¹¹ are taken together with the atom to whichthey are attached to form a cyclopropyl, cyclobutyl, cyclopentyl, orcyclohexyl. In some embodiments, R¹⁰ and R¹¹ are taken together with theatom to which they are attached to form a cyclopropyl.

In certain embodiments, R¹⁰ and R¹¹ are optionally substituted withhalo, alkyl, hydroxy, alkoxy, or fluoroalkyl. In some embodiments, R¹⁰and R¹¹ are optionally substituted with fluoro or C₁₋₆alkyl. In someembodiments, R¹⁰ and R¹¹ are optionally substituted with fluoro ormethyl.

In some embodiments, R¹² is hydrogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆deuteroalkyl, C₃₋₆ carbocyclyl, C₃₋₆ carbocyclylC₁₋₆ alkyl,C₃₋₆heterocyclyl, C₃₋₆ heterocyclylC₁₋₆ alkyl. In some embodiments, R¹²is hydrogen, alkyl, haloalkyl, hydroxy, halo, carbocyclyl, orheteroalkyl. In some embodiments, R¹² is hydrogen, C₁₋₆ alkyl, C₁₋₆fluoroalkyl, carbocyclyl, or heterocyclylalkyl. In certain embodiments,R¹² is C₁₋₆ alkyl or C₁₋₆ fluoroalkyl. In some embodiments, R¹² is C₁₋₆alkyl, C₁₋₆ haloalkyl, C₁₋₆ deuteroalkyl, C₃₋₆ carbocyclyl, C₃₋₆carbocyclylC₁₋₆ alkyl, C₃₋₆ heterocyclyl, C₃₋₆ heterocyclylC₁₋₆ alkyl.In some embodiments, R¹² is alkyl, haloalkyl, hydroxy, halo,carbocyclyl, or heteroalkyl. In some embodiments, R¹² is C₁₋₆ alkyl,C₁₋₆ fluoroalkyl, carbocyclyl, or heterocyclylalkyl. In certainembodiments, R¹² is C₁₋₆ alkyl or C₁₋₆ fluoroalkyl. In certainembodiments, R¹² is hydrogen. In some embodiments, R¹² is C₁₋₆ alkyl. Insome embodiments, R¹² is C₁₋₃ alkyl. In some embodiments, R¹² is C₂₋₈alkyl. In some embodiments, R¹² is C₃₋₆ alkyl. In some embodiments, R¹²is methyl. In some embodiments, R¹² is ethyl. In some embodiments, R¹²is propyl. In some embodiments, R¹² is i-propyl. In some embodiments,R¹² is t-butyl. In some embodiments, R¹² is butyl. In some embodiments,R¹² is isobutyl. In some embodiments, R¹² is sec-butyl. In someembodiments, R¹² is carbocyclyl. In some embodiments, R¹² iscyclopropyl. In some embodiments, R¹² is cyclobutyl. In someembodiments, R¹² is cyclopentyl. In some embodiments, R¹² is cyclohexyl.In some embodiments, R¹² is trifluoromethyl. In some embodiments, R¹² ishydroxyalkyl. In some embodiments, R¹² is deuteromethyl.

In certain embodiments, R¹² is optionally substituted with halo, alkyl,hydroxy, alkoxy, or fluoroalkyl. In some embodiments, R¹² is optionallysubstituted with fluoro C₁₋₆alkyl. In some embodiments, R¹² isoptionally substituted with fluoro or methyl.

In some embodiments, each R¹³ is independently hydrogen, optionallysubstituted alkyl, haloalkyl, optionally substituted carbocyclyl,optionally substituted heteroalkyl, optimally substituted aryl,optionally substituted aralkyl, optionally substituted heterocyclyl, oroptionally substituted heteroaryl. In some embodiments, each R¹³ isindependently hydrogen, optionally substituted alkyl, optionallysubstituted carbocyclyl, optionally substituted heteroalkyl, oroptionally substituted aryl. In some embodiments, each R¹³ isindependently optionally substituted alkyl, optionally substitutedcarbocyclyl, optionally substituted heteroalkyl, optionally substitutedaryl, or heteroaryl. In some embodiments, each R¹³ is independentlyalkyl or aryl. In some embodiments, each R¹³ is independently hydrogenor C₁₋₆ alkyl. In some embodiments, each R¹³ is independently hydrogen,methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, sec-butyl,tert-butyl, pentyl or hexyl. In some embodiments, each R¹³ isindependently hydrogen, methyl, ethyl, propyl, iso-propyl, butyl, ortert-butyl. In some embodiments, each R¹³ is independently hydrogen ormethyl. In some embodiments, R¹³ is H. In other embodiments, R¹³ isalkyl. In other embodiments, R¹³ is aryl.

In some embodiments, n is 0, 1, or 2. In some embodiments, n is 0 or 1.In some embodiments, n is 1 or 2. In some embodiments, n is 3 or 4. Insome embodiments, n is 0. In some embodiments, n is 1. In someembodiments, n is 2. In some embodiments, n is 3.

Any combination of the groups described above for the various variablesis contemplated herein. Throughout the specification, groups andsubstituents thereof are chosen by one skilled in the field to providestable moieties and compounds.

In some embodiments, compounds described herein have the followingstructure of Formula (Ia):

In some embodiments, compounds described herein have the followingstructure of Formula (Ib):

In some embodiments, compounds described herein have the followingstructure of Formula (Ic):

In some embodiments, compounds described herein have the followingstructure of Formula (Id):

In some embodiments, compounds described herein have the followingstructure of Formula (Ie):

In some embodiments, compounds described herein have the followingstructure of Formula (If):

In some embodiments, compounds described herein have the followingstructure of Formula (Ig):

In some embodiments, compounds described herein have the followingstructure of Formula (Ih):

In some embodiments, compounds described herein have the followingstructure of Formula (Ii):

In some embodiments, compounds described herein have the followingstructure of Formula (Ij):

In some embodiments, compounds described herein have the followingstructure of Formula (Ik):

In some embodiments, compounds described herein have the followingstructure of Formula (Im):

In some embodiments, compounds described herein have the followingstructure of Formula (In):

In some embodiments, compounds described herein have the followingstructure of Formula (Io):

In some embodiments, compounds described herein have the followingstructure of Formula (Ip):

In some embodiments, compounds described herein have the followingstructure of Formula (Iq):

In some embodiments, compounds described herein have the followingstructure of Formula (Ir) or Formula (Is):

-   -   wherein    -   ring B is an optionally substituted fused carbocyclyl,        optionally substituted fused heterocyclyl, optionally        substituted fused aryl, or optionally substituted fused        heteroaryl;    -   and n is 0, 1, 2, or 3.

Some embodiments provided herein describe a compound having thestructure of Formula (II), or a pharmaceutically acceptable salt,solvate, or prodrug thereof:

-   wherein-   ring A is a heteroaryl, aryl, cycloalkyl, or heterocyclyl;-   R¹ is —H, —NR⁴R⁵, optionally substituted alkylNR⁴R⁵, halo, —R⁶, —OH,    optionally substituted alkyl, haloalkyl, optionally substituted    carbocyclyl, optionally substituted carbocyclylalkyl, optionally    substituted heteroalkyl, optionally substituted heterocyclyl,    optionally substituted heterocyclylalkyl, optionally substituted    hydroxyalkyl, optionally substituted aryl, optionally substituted    heteroaryl, —C(O)OR⁶, —C(O)NR⁴R⁵, —OC(O)OR⁶, —OC(O)NR⁴R⁵,    —S(O)₂NR⁴R⁵, —S(O)₂R⁷, —S(O)R⁷, —SR⁷, —NR⁴S(O)₂NR⁴R⁵, —P(O)(OR⁶)₂,    —P(O(R⁶)₂, —CN, —CO₂H, or —NO₂;-   each R² is independently —NR⁴R⁵, optionally substituted alkylNR⁴R⁵,    halo, —OR⁶, —OH, optionally substituted alkyl, haloalkyl, optionally    substituted carbocyclyl, optionally substituted carbocyclylalkyl,    optionally substituted heteroalkyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, optionally    substituted hydroxyalkyl, —C(O)R⁶, —C(O)OR⁶, —C(O)NR⁴R⁵, —OC(O)OR⁶,    —OC(O)NR⁴R⁵, —S(O)₂NR⁴R⁵, —S(O)₂R⁷, —S(O)R⁷, —SR⁷, —NR⁴S(O)₂NR⁴R⁵,    —CN, —CO₂H, or —NO₂;-   R³ is optionally substituted alkyl, halo, haloalkyl, optionally    substituted carbocyclyl, optionally substituted carbocyclylalkyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heteroalkyl, optionally    substituted aryl, optionally substituted heteroaryl, —Si(R⁶)₃, —OR⁶,    or —S(O)₂R⁷;-   R⁴ and R⁵ are each independently —H, optionally substituted alkyl,    haloalkyl, optionally substituted carbocyclyl, optionally    substituted aryl, optionally substituted heterocyclyl, optionally    substituted heteroaryl, —S(O)₂R⁷, —C(O)N(R¹³)₂, —C(O)R⁶, or    —C(O)OR⁶;    -   or R⁴ and R⁵ attached to the same N atom are taken together with        the N atom to which they are attached to form a substituted or        unsubstituted heterocycle;-   each R⁶ is independently optionally substituted alkyl, haloalkyl,    optionally substituted carbocyclyl, optionally substituted aryl,    optionally substituted heterocyclyl, or optionally substituted    heteroaryl;-   R⁷ is optionally substituted alkyl, haloalkyl, optionally    substituted carbocyclyl, optionally substituted heteroalkyl,    optionally substituted aryl, optionally substituted aralkyl,    optionally substituted heterocyclyl, or optionally substituted    heteroaryl;-   each R¹³ is independently H, optionally substituted alkyl,    haloalkyl, optionally substituted carbocyclyl, optionally    substituted heteroalkyl, optionally substituted aryl, optionally    substituted aralkyl, optionally substituted heterocyclyl, or    optionally substituted heteroaryl;-   R¹⁴ is hydrogen or methyl;-   and n is 0, 1, 2, 3, or 4.

In some embodiments,

-   ring A is aryl or bicyclic heteroaryl;-   R¹ is —NR⁴R⁵, halo, —OR⁶, C₁₋₆alkyl, C₁₋₆fluoroalkyl,    C₃₋₆carbocyclyl, C₃₋₆heterocyclyl, aryl, heteroaryl, —C(O)NR⁴R⁵,    —S(O)₂NR⁴R⁵, —S(O)₂R⁷, —NR⁴S(O)₂NR⁴R⁵, —P(O)(R⁶)₂, —P(O)(OR⁶)₂, or    —CN;-   each R² is independently —NR⁴R⁵, halo, —OR⁶, C₁₋₆alkyl,    C₁₋₆fluoroalkyl, C₃₋₆carbocyclyl, C₁₋₆heteroalkyl, C₃₋₆heterocyclyl,    or —CN;-   R³ is C₁₋₆ alkyl, C₁₋₆ fluoroalkyl, carbocyclyl, or    heterocyclylalkyl;-   R⁴ and R⁵ are each independently —H, C₁₋₆ alkyl, C₁₋₆ fluoroalkyl,    C₃₋₆ carbocyclyl, C₁₋₆ carbocyclylalkyl, C₂₋₆ heterocyclyl, C₁₋₆    alkylC₃₋₆heterocyclyl, —S(O)₂R⁷, or —C(O)N(R¹³);    -   or R⁴ and R⁵ attached to the same N atom are taken together with        the N atom to which they are attached to form a substituted or        unsubstituted 4-, 5-, or 6-membered heterocycle;-   R⁶ is alkyl;-   R⁷ is C₁₋₆alkyl, C₃₋₆carbocyclyl, or phenyl optionally substituted    with halo or alkyl;-   each R¹³ is independently hydrogen or C₁₋₆ alkyl;-   R¹⁴ is hydrogen or methyl;-   and n is 0, 1, 2, 3, or 4.

In some embodiments,

-   ring A is phenyl, 3-benzodioxyxlyl, or 1,4-benzodioxanyl;-   R¹ is —NR⁴R⁵, halo, —OR⁶, alkyl, or fluoroalkyl;-   each R² is independently —NR⁴R⁵, halo, alkyl, carbocyclyl, alkoxy,    or —CN;-   R³ is C₁₋₆ alkyl, C₁₋₆ fluoroalkyl, carbocyclyl, deuteroalkyl, or    heteroalkyl;-   R⁴ and R⁵ are each independently —H, C₁₋₆alkyl, heteroalkyl, or    —S(O)R⁷;-   or R⁴ and R⁵ attached to the same N atom are taken together with the    N atom to which they are attached to form a substituted or    unsubstituted 4-, 5-, or 6-membered heterocycle;-   R⁶ is alkyl;-   R⁷ is C₁₋₆alkyl, C₃₋₆carbocyclyl, or phenyl optionally substituted    with halo or alkyl;-   each R¹³ is independently hydrogen or C₁₋₆ alkyl;-   R¹⁴ is hydrogen;-   and n is 0, 1, or 2.

In some embodiments,

-   ring A is phenyl;-   R¹ is —NR⁴R⁵, —OR⁶, alkyl, or fluoroalkyl;-   each R² is independently —NR⁴R⁵, halo, alkyl;-   R³ is C₁₋₆ alkyl, C₁₋₆ fluoroalkyl, carbocyclyl, deuteroalkyl, or    heteroalkyl;-   R⁴ and R⁵ are each independently —H, C₁₋₆alkyl, or heteroalkyl;    -   or R⁴ and R⁵ attached to the same N atom are taken together with        the N atom to which they are attached to form a substituted or        unsubstituted 4-, 5-, or 6-membered heterocycle;-   R⁶ is alkyl;-   R⁷ is C₁₋₆alkyl, C₃₋₆carbocyclyl, or phenyl optionally substituted    with halo or alkyl;-   each R¹³ is independently hydrogen or C₁₋₆ alkyl;-   R¹⁴ is hydrogen;-   and n is 0, 1, or 2.

In some embodiments,

-   ring A is 3-benzodioxyxlyl, or 1,4-benzodioxanyl;-   R¹ is —H;-   R³ is C₁₋₆ alkyl;-   each R¹³ is independently hydrogen or C₁₋₆ alkyl;-   R¹⁴ is hydrogen;-   and n is 0.

For any and all of the embodiments of Formula (II), substituents areselected from among a subset of the listed alternatives.

In some embodiments, ring A is monocyclic aryl, bicyclic aryl,monocyclic heteroaryl, or bicyclic heteroaryl. In some embodiments, ringA is monocyclic heteroaryl or monocyclic aryl. In some embodiments, ringA is bicyclic heteroaryl or bicyclic aryl. In some embodiments, ring Ais N-bound heteroaryl. In some embodiments, ring A is C-boundheteroaryl. In some embodiments, ring A is aryl.

In certain embodiments, ring A is phenyl, naphthyl, furanyl, pyrrolyl,oxazolyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl,isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl,pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, quinolinyl,isoquinolinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, indolyl,indazolyl, benzoxazolyl, benzisoxazolyl, benzofuranyl, benzothienyl,benzothiazolyl, benzimidazolyl, purinyl, cinnolinyl, phthalazinyl,pteridinyl, pyridopyrimidinyl, pyrazolopyrimidinyl, or azaindolyl. Insome embodiments, R¹ is furanyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl,oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl,pyridazinyl, or triazinyl. In some embodiments, ring A is pyrimidinyl,pyridinyl, pyridinyl, triazinyl, or thiazolyl. In certain embodiments,ring A is C-bound imidazolyl. In certain embodiments, ring A is N-boundimidazolyl. In some embodiments, ring A is pyrimidinyl. In someembodiments, ring A is pyrimidinyl optionally substituted with alkyl oralkoxy. In some embodiments, ring A is pyrazinyl. In some embodiments,ring A is triazinyl. In some embodiments, ring A is thiazolyl.

In some embodiments, ring A is phenyl, pyridinyl, pyrimidinyl,pyrazinyl, or pyridazinyl. In some embodiments, ring A is phenyl.

In some embodiments, ring A is a bicyclic heteroaryl. In certainembodiments, ring A is an optionally substituted 3-benzodioxyxlyl or1,4-benzodioxanyl. In some embodiments, ring A is an unsubstituted3-benzodioxyxlyl or 1,4-benzodioxanyl.

In some embodiments, R¹ is —H, —NR⁴R⁵, optionally substitutedalkylNR⁴R⁵, halo, optionally substituted alkyl, fluoroalkyl, optionallysubstituted carbocyclyl, optionally substituted carbocyclylalkyl,optionally substituted heterocyclyl, optionally substitutedheterocyclylalkyl, optionally substituted hydroxyalkyl, optionallysubstituted aryl, optionally substituted heteroaryl, —C(O)NR⁴R⁵,—OC(O)OR⁶, —OC(O)NR⁴R⁵, —S(O)₂NR⁴R⁵, —S(O)₂R⁷, —S(O)R⁷, —SR⁷,—NR⁴S(O)₂NR⁴R⁵, —P(O)(OR⁶)₂, —P(O)(R⁶)₂, —CN, or —NO₂. In someembodiments, R¹ is —H, —NR⁴R⁵, halo, —OR⁶, optionally substituted alkyl,fluoroalkyl, optionally substituted carbocyclyl, optionally substitutedheterocyclyl, optionally substituted aryl, optionally substitutedheteroaryl, —C(O)NR⁴R⁵, —S(O)₂NR⁴R⁵, —S(O)₂R⁷, —NR⁴S(O)₂NR⁴R⁵,—P(O)(R⁶)₂, —P(O)(OR⁶)₂, or —CN. In some embodiments, R¹ is —H, —NR⁴R⁵,optionally substituted alkylNR⁴R⁵, halo, —OR⁶, optionally substitutedalkyl, fluoroalkyl, optionally substituted carbocyclyl, optionallysubstituted heteroalkyl, optionally substituted heterocyclyl, —C(O)R⁶,—C(O)NR⁴R⁵, —S(O)₂NR⁴R⁵, —S(O)₂R⁷, —NR⁴S(O)₂NR⁴R⁵, —CN, or —CO₂H. Insome embodiments, R¹ is —NR⁴R⁵, halo, —OR⁶, alkyl, fluoroalkyl,carbocyclyl, heteroalkyl, heterocyclyl, —S(O)₂NR⁴R⁵, —S(O)₂R⁷,—NR⁴S(O)₂NR⁴R⁵, or —CN. In some embodiments, R¹ is NR⁴R⁵, halo, —OR⁶,C₁₋₆alkyl, C₁₋₆fluoroalkyl, C₃₋₆carbocyclyl, C₃₋₆heterocyclyl, aryl,heteroaryl, —C(O)NR⁴R⁵, —S(O)₂NR⁴R⁵, —S(O)₂R⁷, —NR⁴S(O)₂NR⁴R⁵,—P(O)(R⁶)₂, —P(O)(OR⁶)₂, or —CN. In some embodiments, R¹ is —NR⁴R⁵,halo, —OR⁶, —S(O)₂NR⁴R⁵, —P(O)(R⁶)₂, or —P(O)(OR⁶)₂. In certainembodiments, R¹ is —NR⁴R⁵, halo, —OR⁶, alkyl, or fluoroalkyl. In certainembodiments, R¹ is halo, —OR⁶, or alkyl. In other embodiments, R¹ is—NMe₂, —NHMe, —NH₂, methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl,sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, iso-propoxy,morpholino, or pyrrolidino. In certain embodiments, R¹ is C₁₋₆alkyl,fluoroalkyl, C₃₋₆carbocyclyl, or C₃₋₆heterocyclyl. In some embodiments,R¹ is —H. In some embodiments, R¹ is —NR⁴R⁵. In some embodiments, R¹ is—NMe₂. In some embodiments, R¹ is —NHMe. In some embodiments, R¹ is—NH₂. In some embodiments, R¹ is —NMeEt. In some embodiments, R¹ is—NEt₂. In some embodiments, R¹ is halo. In some embodiments, R¹ isfluoro. In some embodiments, R¹ is chloro. In some embodiments, R¹ isbromo. In some embodiments, R¹ is C₁₋₆alkyl. In some embodiments, R¹ ismethyl. In some embodiments, R¹ is ethyl. In some embodiments, R¹ ispropyl. In some embodiments, R¹ is iso-propyl. In some embodiments, R¹is carbocyclyl. In some embodiments, R¹ is cyclopropyl. In someembodiments, R¹ is cyclobutyl. In some embodiments, R¹ is cyclopentyl.In some embodiments, R¹ is cyclohexyl. In some embodiments, R¹ is —OR⁶.In some embodiments, R¹ is methoxy. In some embodiments, R¹ is ethoxy.In some embodiments, R¹ is propoxy. In some embodiments, R¹ isiso-propoxy. In some embodiments, R¹ is heterocyclyl. In someembodiments, R¹ is azetadino, morpholino, thiomorpholino, piperidino,piperazino, or pyrrolidino. In some embodiments, R¹ is morpholino. Insome embodiments, R¹ is pyrrolidino. In some embodiments, R¹ isazetidino.

In other embodiments, R¹ is optionally substituted monocyclic aryl,optionally substituted bicyclic aryl, optionally substituted monocyclicheteroaryl, or optionally substituted bicyclic heteroaryl. In certainembodiments, R¹ is phenyl, naphthyl, furanyl, pyrrolyl, oxazolyl,thiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl,isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl,pyrazinyl, pyridazinyl, triazinyl, quinolinyl, isoquinolinyl,quinazolinyl, quinoxalinyl, naphthyridinyl, indolyl, indazolyl,benzoxazolyl, benzisoxazolyl, benzofuranyl, benzothienyl,benzothiazolyl, benzimidazolyl, purinyl, cinnolinyl, phthalazinyl,pteridinyl, pyridopyrimidinyl, pyrazolopyrimidinyl, or azaindolyl. Insome embodiments, R¹ is furanyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl,oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl,pyridazinyl, or triazinyl. In some embodiments, R¹ is pyrimidinyl,pyridinyl, pyrazinyl, triazinyl, or thiazolyl. In certain embodiments,R¹ is C-bound imidazolyl. In certain embodiments, R¹ is N-boundimidazolyl. In some embodiments, R¹ is pyrimidinyl. In some embodiments,R¹ is pyrimidinyl optionally substituted with alkyl or alkoxy. In someembodiments, R¹ is pyrazinyl. In some embodiments, R¹ is triazinyl. Insome embodiments, R¹ is thiazolyl.

In certain embodiments, R¹ is optionally substituted with halo, alkyl,hydroxy, alkoxy, or fluoroalkyl. In certain embodiments, R¹ isoptionally substituted with halo, alkyl, or alkoxy. In some embodiments,R¹ is optionally substituted with fluoro or C₁₋₆alkyl. In someembodiments, R¹ is optionally substituted with fluoro or methyl. In someembodiments, R¹ is optionally substituted with methyl or methoxy.

In some embodiments, each R² is independently —NR⁴R⁵, optionallysubstituted alkylNR⁴R⁵, halo, —OR⁶, —OH, optionally substituted alkyl,haloalkyl, optionally substituted carbocyclyl, optionally substitutedcarbocyclylalkyl, optionally substituted heteroalkyl, optionallysubstituted heterocyclyl, optionally substituted heterocyclylalkyl,optionally substituted hydroxyalkyl, —C(O)R⁶, —(O)NR⁴R⁵, —S(O)₂NR⁴R⁵,—S(O)₂R⁷, —NR⁴S(O)₂NR⁴R⁵, or —CN. In some embodiments, each R² isindependently —NR⁴R⁵, alkylNR⁴R⁵, halo, —OR⁶, —OH, alkyl, haloalkyl,carbocyclyl, carbocyclylalkyl, heteroalkyl, heterocyclyl,heterocyclylalkyl, hydroxyalkyl, —C(O)R⁶, —C(O)NR⁴R⁵, —S(O)NR⁴R⁵,—S(O)₂R⁷, —NR⁴S(O)₂NR⁴R⁵, or —CN. In some embodiments, —NR⁴R⁵, halo,—OR⁶, optionally substituted alkyl, fluoroalkyl, optionally substitutedcarbocyclyl, optionally substituted heteroalkyl, optionally substitutedheterocyclyl, —C(O)NR⁴R⁵, —S(O)₂NR⁴R⁵, —S(O)₂R⁷, —NR⁴S(O)₂NR⁴R⁵, —CN, or—CO₂H. In certain embodiments, each R² is independently —NR⁴R⁵, halo,—OR⁶, —OH, optionally substituted alkyl, fluoroalkyl, optionallysubstituted carbocyclyl, optionally substituted heteroalkyl, optionallysubstituted heterocyclyl, optionally substituted hydroxyalkyl,—S(O)₂NR⁴R⁵, —S(O)₂R⁷, —NR⁴S(O)₂NR⁴R⁵, or —CN. In some embodiments, eachR² is independently —NR⁴R⁵, halo, —OR⁶, alkyl, fluoroalkyl, carbocyclyl,heteroalkyl, heterocyclyl, —S(O)₂NR⁴R⁵, —NR⁴S(O)₂NR⁴R⁵, or —S(O)₂R⁷. Insome embodiments, each R² is independently —NR⁴R⁵, C₁₋₆alkylNR⁴R⁵, halo,—OR⁶, —OH, C₁₋₆alkyl, C₁₋₆fluoroalkyl, C₃₋₆carbocyclyl,C₁₋₆alkylC₃₋₆carbocyclyl, C₁₋₆heteroalkyl, C₃₋₆heterocyclyl,C₁₋₆alkylC₃₋₆heterocyclyl, C₁₋₆hydroxyalkyl, or —CN. In someembodiments, each R² is independently —C(O)R⁶, —C(O)NR⁴R⁵, —S(O)₂NR⁴R⁵,—S(O)₂R⁷, or —CN. In some embodiments, each R² is independently —NR⁴R⁵,halo, —OR⁶, C₁₋₆alkyl, C₁₋₆fluoroalkyl, C₃₋₆carbocyclyl,C₁₋₆heteroalkyl, C₃₋₆heterocyclyl, or —CN. In some embodiments, each R²is independently —NR⁴R⁵, halo, alkyl, carbocyclyl, alkoxy, or —CN. Insome embodiments, each R² is independently —NR⁴R⁵, halo, alkyl, oralkoxy. In some embodiments, each R² is independently methyl, methoxy,ethyl, propyl, iso-propyl, cyclopropyl, fluoro, chloro, or —NMe₂. Insome embodiments, each R² is independently methyl, methoxy, iso-propyl,cyclopropyl, fluoro, chloro, or —NMe₂. In some embodiments, R² ismethoxy. In some embodiments, R² is methyl. In some embodiments R² isethyl. In some embodiments, R² is iso-propyl. In some embodiments, R² ispropyl. In some embodiments, R² is cyclopropyl. In some embodiments, R²is cyclobutyl. In some embodiments, R² is fluoro. In some embodiments,R² is chloro. In some embodiments, R² is —NMe₂. In some embodiments, R²is —NH₂. In some embodiments, R² is —NHMe. In some embodiments, R² is—NMeEt.

In certain embodiments, each R² is independently optionally substitutedwith halo, alkyl, hydroxy, alkoxy, or fluoroalkyl. In some embodiments,each R² is independently optionally substituted with fluoro orC₁₋₆alkyl. In some embodiments, each R² is independently optionallysubstituted with fluoro or methyl.

In some embodiments, R³ is alkyl, halo, haloalkyl, deuteroalkyl,carbocyclyl, carbocyclylalkyl, heterocyclyl, heterocyclylalkyl, aryl,heteroaryl, —Si(R⁶)₃, —OR⁶, or —S(O)₂R⁷. In some embodiments, R³ isalkyl, halo, haloalkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl,heterocyclylalkyl, or heteroalkyl. In some embodiments, R³ is optionallysubstituted C₁₋₁₀alkyl, halo, haloalkyl, deuteroalkyl, carbocyclyl,optionally substituted aryl, or optionally substituted heteroaryl,wherein R³ is optionally substituted with halo, alkyl, alkoxy, hydroxy,—NR⁴R⁵, or —S(O)₂R⁷. In some embodiments, R³ is C₁₋₆alkyl,C₁₋₆haloalkyl, C₁₋₆deuteroalkyl, C₃₋₆ carbocyclyl, C₃₋₆carbocyclylC₁₋₆alkyl, C₃₋₆heterocyclyl, C₃₋₆ heterocyclylC₁₋₆ alkyl. Insome embodiments, R³ is alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl,heterocyclyl, heterocyclylalkyl, or heteroalkyl. In some embodiments, R³is C₁₋₆ alkyl, C₁₋₆ fluoroalkyl, carbocyclyl, or heterocyclylalkyl. Incertain embodiments, R³ is C₃₋₈ alkyl or C₁₋₆ fluoroalkyl. In someembodiments, R³ is C₁₋₆ alkyl. In some embodiments, R³ is C₁₋₈ alkyl. Insome embodiments, R³ is C₂₋₈ alkyl. In some embodiments, R³ is C₃₋₆alkyl. In some embodiments, R³ is methyl. In some embodiments, R³ isethyl. In some embodiments, R³ is propyl. In some embodiments, R³ isi-propyl. In some embodiments, R³ is t-butyl. In some embodiments, R³ isbutyl. In some embodiments, R³ is isobutyl. In some embodiments, R³ issec-butyl. In some embodiments, R³ is carbocyclyl. In some embodiments,R³ is cyclopropyl. In some embodiments, R³ is cyclobutyl. In someembodiments, R³ is cyclopentyl. In some embodiments, R³ is cyclohexyl.In some embodiments, R³ is halo. In some embodiments, R³ is fluoro. Insome embodiments, R³ is chloro. In some embodiments, R³ is bromo. Insome embodiments, R³ is trifluoromethyl. In some embodiments, R³ ishydroxyalkyl. In some embodiments, R³ is deuteromethyl. In someembodiments, R³ is —Si(R⁶)₃. In some embodiments, R³ is —Si(Me)₃. Insome embodiments, R³ is —Si(Ph)₃. In some embodiments, R³ is —OR⁶. Insome embodiments, R³ is —S(O)₂R⁷.

In other embodiments, R³ is optionally substituted aryl or optionallysubstituted heteroaryl. In certain specific embodiments, R³ is phenyl,furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl,triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl,thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, ortriazinyl. In some embodiments, R³ is phenyl optionally substituted withhalo, alkyl, alkoxy, hydroxy, —NR⁴R⁵, or —S(O)₂R⁷. In some embodiments,R³ is pyridinyl optionally substituted with halo, alkyl, alkoxy,hydroxy, —NR⁴R⁵, or —S(O)₂R⁷. In some embodiments, R³ is phenyl. In someembodiments, R³ is pyridinyl.

In certain embodiments, R³ is optionally substituted with halo, alkyl,hydroxy, alkoxy, —NR⁴R⁵, —S(O)₂R⁷ or fluoroalkyl. In some embodiments,R³ is optionally substituted with chloro, fluoro, methyl, ethyl, propyl,iso-propyl, butyl, iso-butyl, sec-butyl, tert-butyl, hydroxy, methoxy,ethoxy, propoxy, iso-propoxy, dimethylamino, diethylamino, methylamino,amino, —S(O)₂Me, or trifluoromethyl. In certain embodiments, R³ isoptionally substituted with chloro, fluoro, methyl, hydroxy, methoxy,dimethylamino, —S(O)₂Me, or trifluoromethyl.

In some embodiments, R⁴ and R⁵ are each independently —H, optionallysubstituted alkyl, fluoroalkyl, optionally substituted carbocyclyl,optionally substituted carbocyclylalkyl, optionally substitutedheterocyclyl, optionally substituted heterocyclylalkyl, —S(O)₂R⁷, or—C(O)N(R¹³)₂. In some embodiments, R⁴ and R⁵ are each independently —H,C₁₋₆ alkyl, C₁₋₆ fluoroalkyl, C₃₋₆ carbocyclyl, C₁₋₆ carbocyclylalkyl,C₂₋₆ heterocyclyl, C₁₋₆ alkylC₃₋₆heterocyclyl, —S(O)₂R⁷, or—C(O)N(R¹³)₂. In some embodiments, R⁴ and R⁵ are each independently —H,C₁₋₆alkyl, C₁₋₆fluoroalkyl, C₃₋₆carbocyclyl, C₃₋₅heterocyclyl, or—S(O)₂R⁷. In some embodiments, R⁴ and R⁵ are each independently —H,C₁₋₆alkyl, or —S(O)₂R⁷. In some embodiments, R⁴ and R⁵ are eachindependently —H, methyl, ethyl, propyl, iso-propyl, butyl, sec-butyl,iso-butyl, tert-butyl, or —S(O)₂R⁷. In some embodiments, R⁴ and R⁵ areeach independently —H, methyl, ethyl, propyl, or iso-propyl. In someembodiments, R⁴ and R⁵ are —H. In some embodiments, R⁴ and R⁵ aremethyl. In some embodiments, R⁴ is methyl and R⁵ is ethyl. In someembodiments, R⁴ is methyl and R⁵ is propyl. In some embodiments, R⁴ ismethyl and R⁵ is iso-propyl. In some embodiments, R⁴ is H and R⁵ isiso-propyl. In some embodiments, R⁴ and R⁵ are each independently —H or—C(O)N(R¹³)₂.

In other embodiments, R⁴ and R⁵ attached to the same N atom are takentogether with the N atom to which they are attached to form asubstituted or unsubstituted 4-, 5-, or 6-membered ring heterocycleadditionally containing 0-3 heteroatoms selected from —O—, —NH—, —NR⁶—,—S—, and —S(O)₂—. In some embodiments, R⁴ and R⁵ attached to the same Natom are taken together with the N atom to which they are attached toform a 4-, 5- or 6-membered heterocycle additionally containing 0 or 1oxygen heteroatom. In other embodiments, R⁴ and R⁵ attached to the sameN atom are taken together with the N atom to which they are attached toform a substituted or unsubstituted 4-, 5-, or 6-membered ringheterocycle additionally containing 1 heteroatoms selected from —O—,—NH—, —NR⁶—, —S—, and —S(O)₂—. In other embodiments, R⁴ and R⁵ attachedto the same N atom are taken together with the N atom to which they areattached to form a 4-, 5-, or 6-membered ring heterocycle additionallycontaining 1 oxygen heteroatom. In other embodiments, R⁴ and R⁵ attachedto the same N atom are taken together with the N atom to which they areattached to form a 4-, 5-, or 6-membered ring. In some embodiments, the4-, 5-, or 6-membered ring is

In certain embodiments, R⁴ and R⁵ are each independently optionallysubstituted with halo, alkyl, hydroxy, alkoxy, or fluoroalkyl. In someembodiments, R⁴ and R⁵ are each independently optionally substitutedwith fluoro or C₁₋₆alkyl. In some embodiments, R⁴ and R⁵ are eachindependently optionally substituted with fluoro or methyl.

In some embodiments, R⁶ is optionally substituted alkyl, fluoroalkyl,optionally substituted aryl, optionally substituted carbocyclyl, oroptionally substituted heterocyclyl. In some embodiments, R⁶ isoptionally substituted alkyl, fluoroalkyl, optionally substitutedcarbocyclyl, or optionally substituted heterocyclyl. In someembodiments, R⁶ is alkyl, aryl, carbocyclyl, or heterocyclyl. In someembodiments, R⁶ is alkyl, carbocyclyl, or heterocyclyl. In someembodiments, R⁶ is alkyl, carbocyclyl, or fluoroalkyl. In someembodiments, R⁶ is C₁₋₆alkyl, C₁₋₆fluoroalkyl, C₃₋₆carbocyclyl, orC₃₋₆heterocyclyl. In certain embodiments, R⁶ is C₁₋₆alkyl. In certainembodiments, R⁶ is methyl, ethyl, propyl, iso-propyl, butyl, sec-butyl,iso-butyl, or tert-butyl. In some embodiments, R⁶ is optionallysubstituted phenyl.

In some embodiments, R⁷ is alkyl, carbocyclyl, optionally substitutedaryl, optionally substituted aralkyl, or optionally substitutedheterocyclyl. In some embodiments, R⁷ is C₁₋₆alkyl, C₃₋₆carbocyclyl, oraryl optionally substituted with halo or alkyl. In some embodiments, R⁷is C₁₋₆alkyl, C₃₋₆carbocyclyl, or phenyl optionally substituted withhalo or alkyl. In some embodiments, R⁷ is optionally substituted benzyl.In some embodiments, R⁷ is C₃₋₆carbocyclyl. In some embodiments, R⁷ isphenyl. In some embodiments, R⁷ is phenyl substituted with 1-4 C₁₋₆alkylor fluoro substituents. In some embodiments, R⁷ is phenyl substitutedwith a C₁₋₆alkyl or fluoro substituent. In some embodiments, R⁷ isalkyl, carbocyclyl, aralkyl, or heterocyclyl.

In certain embodiments, R⁷ is optionally substituted with halo, alkyl,hydroxy, alkoxy, or fluoroalkyl. In some embodiments, R⁷ is optionallysubstituted with fluoro or C₁₋₆alkyl. In some embodiments, R⁷ isoptionally substituted with fluoro or methyl.

In some embodiments, each R¹³ is independently hydrogen, optionallysubstituted alkyl, haloalkyl, optionally substituted carbocyclyl,optionally substituted heteroalkyl, optionally substituted aryl,optionally substituted aralkyl, optionally substituted heterocyclyl, oroptionally substituted heteroaryl. In some embodiments, each R¹³ isindependently hydrogen, optionally substituted alkyl, optionallysubstituted carbocyclyl, optionally substituted heteroalkyl, oroptionally substituted aryl. In some embodiments, each R¹³ isindependently optionally substituted alkyl, optionally substitutedcarbocyclyl, optionally substituted heteroalkyl, optionally substitutedaryl, or heteroaryl. In some embodiments, each R¹³ is independentlyalkyl or aryl. In some embodiments, each R¹³ is independently hydrogenor C₁₋₆ alkyl. In some embodiments, each R¹³ is independently hydrogen,methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, sec-butyl,tert-butyl, pentyl or hexyl. In some embodiments, each R¹³ isindependently hydrogen, methyl, ethyl, propyl, iso-propyl, butyl, ortert-butyl. In some embodiments, each R¹³ is independently hydrogen ormethyl. In some embodiments, R¹³ is H. In other embodiments, R¹³ isalkyl. In other embodiments, R¹³ is aryl.

In some embodiments, R¹⁴ is hydrogen or methyl.

In some embodiments, n is 0, 1, or 2. In some embodiments, n is 0 or 1.In some embodiments, n is 1 or 2. In some embodiments, n is 3 or 4. Insome embodiments, n is 0. In some embodiments, n is 1. In someembodiments, n is 2. In some embodiments, n is 3.

In some embodiments,

-   ring A is a monocyclic or bicyclic heteroaryl, monocyclic or    bicyclic aryl, monocyclic cycloalkyl, or monocyclic heterocyclyl;-   R¹ is —H, —NR⁴R⁵, optionally substituted alkylNR⁴R⁵, halo, —OR⁶,    —OH, optionally substituted alkyl, haloalkyl, optionally substituted    carbocyclyl, optionally substituted heteroalkyl, optionally    substituted heterocyclyl, optionally substituted hydroxyalkyl,    —C(O)NR⁴R⁵, —S(O)₂NR⁴R⁵, —S(O)₂R⁷, —NR⁴S(O)₂NR⁴R⁵, —P(O)(OR⁶)₂, —CN,    or —CO₂H;-   each R² is independently —NR⁴R⁵, optionally substituted alkylNR⁴R⁵,    halo, —OR⁶, —OH, optionally substituted alkyl, haloalkyl, optionally    substituted carbocyclyl, optionally substituted heteroalkyl,    optionally substituted heterocyclyl, optionally substituted    hydroxyalkyl, —C(O)NR⁴R⁵, —S(O)₂NR⁴R⁵, —S(O)₂R⁷, —NR⁴S(O)₂NR⁴R⁵,    —CN, or —CO₂H;-   R³ is optionally substituted alkyl, halo, haloalkyl, deuteroalkyl,    optionally substituted carbocyclyl, optionally substituted    carbocyclylalkyl, optionally substituted heterocyclyl, optionally    substituted heterocyclylalkyl, optionally substituted heteroalkyl,    optionally substituted aryl, optionally substituted heteroaryl,    —Si(R⁶)₃, —OR⁶, or —S(O)₂R⁷;-   R⁴ and R⁵ are each independently —H, optionally substituted alkyl,    haloalkyl, optionally substituted carbocyclyl, optionally    substituted aryl, optionally substituted heterocyclyl, optionally    substituted heteroaryl, —S(O)₂R⁷, —C(O)N(R¹³)₂, —C(O)R⁶, or    —C(O)OR⁶;    -   or R⁴ and R⁵ attached to the same N atom are taken together with        the N atom to which they are attached to form a substituted or        unsubstituted 4-, 5-, or 6-membered heterocycle;-   R⁶ is optionally substituted alkyl, haloalkyl, optionally    substituted carbocyclyl, optionally substituted aryl, optionally    substituted heterocyclyl, or optionally substituted heteroaryl;-   R⁷ is optionally substituted alkyl, haloalkyl, optionally    substituted carbocyclyl, optionally substituted heteroalkyl,    optionally substituted aryl, optionally substituted aralkyl,    optionally substituted heterocyclyl, or optionally substituted    heteroaryl;-   each R¹³ is independently H, optionally substituted alkyl,    haloalkyl, optionally substituted carbocyclyl, optionally    substituted heteroalkyl, optionally substituted aryl, optionally    substituted aralkyl, optionally substituted heterocyclyl, or    optionally substituted heteroaryl;-   R¹⁴ is hydrogen or methyl;-   and n is 0, 1, 2, 3, or 4.

In some embodiments, ring A is a monocyclic or bicyclic aryl; R¹ is —H,—NR⁴R⁵, optionally substituted alkylNR⁴R⁵, halo, —OR⁶, —OH, optionallysubstituted alkyl, haloalkyl, or optionally substituted carbocyclyl;each R² is independently —NR⁴R⁵, optionally substituted alkylNR⁴R⁵,halo, —OR⁶, —OH, or optionally substituted alkyl; R³ is optionallysubstituted alkyl, halo, haloalkyl, deuteroalkyl, optionally substitutedcarbocyclyl, optionally substituted carbocyclylalkyl, optionallysubstituted heterocyclyl, or —S(O)₂R⁷; R⁴ and R⁵ are each independently—H, optionally substituted alkyl, haloalkyl, optionally substitutedcarbocyclyl, optionally substituted aryl, or —C(O)OR⁶; R⁶ is optionallysubstituted alkyl; R⁷ is optionally substituted alkyl; each R¹³ isindependently H, optionally substituted alkyl, haloalkyl, optionallysubstituted carbocyclyl, or optionally substituted heteroalkyl; R¹⁴ ishydrogen or methyl; and n is 0, 1, 2, 3, or 4.

In some embodiments, ring A is a monocyclic or bicyclic heteroaryl,monocyclic or bicyclic aryl; and R¹ is —H, —NR⁴R⁵, optionallysubstituted alkylNR⁴R⁵, halo, —OR⁶, —OH optionally substituted alkyl,haloalkyl, optionally substituted hydroxyalkyl, —C(O)NR⁴R⁵, —S(O)₂NR⁴R⁵,—S(O)₂R⁷, —NR⁴S(O)₂NR⁴R⁵, —P(O)(OR⁶)₂, —CN, or —CO₂H. In someembodiments, ring A is a monocyclic or bicyclic heteroaryl, monocyclicor bicyclic aryl; and R¹ is —H, —NR⁴R⁵, optionally substitutedalkylNR⁴R⁵, halo, —OR⁶, —OH, optionally substituted alkyl, or —CO₂H. Insome embodiments, ring A is a monocyclic or bicyclic aryl; and R¹ is —H,—NR⁴R⁵, optionally substituted alkylNR⁴R⁵, halo, —OR⁶, —OH, optionallysubstituted alkyl, or —CO₂H. In some embodiments, ring A is a monocyclicor bicyclic aryl; and R¹ is —H, —NR⁴R⁵, optionally substitutedalkylNR⁴R⁵, halo, —OH, or —CO₂H.

In some embodiments, ring A is a monocyclic or bicyclic heteroaryl,monocyclic or bicyclic aryl, monocyclic cycloalkyl, or monocyclicheterocyclyl; R¹ is —H, —NR⁴R⁵, optionally substituted alkylNR⁴R⁵, halo,optionally substituted alkyl, haloalkyl, optionally substitutedcarbocyclyl, optionally substituted hydroxyalkyl, —C(O)NR⁴R⁵,—S(O)₂NR⁴R⁵, —S(O)₂R⁷, —NR⁴S(O)₂NR⁴R⁵, —P(O)(OR⁶)₂, —CN, or —CO₂H; andR³ is optionally substituted alkyl, halo, haloalkyl, deuteroalkyl,optionally substituted aryl, optionally substituted heteroaryl,—Si(R⁶)₃, —OR⁶, or —S(O)₂R⁷. In some embodiments, ring A is a monocyclicor bicyclic aryl; R¹ is —H, —NR⁴R⁵, optionally substituted alkylNR⁴R⁵,—C(O)NR⁴R⁵, —S(O)₂NR⁴R⁵, —S(O)₂R⁷, —NR⁴S(O)₂NR⁴R⁵, —P(O)(OR⁶)₂, —CN, or—CO₂H; R³ is optionally substituted alkyl, halo, optionally substitutedheteroaryl, —Si(R⁶)₃, —OR⁶, or —S(O)₂R⁷; and R⁴ and R⁵ are eachindependently —H, optionally substituted alkyl, or —C(O)OR⁶.

In some embodiments, ring A is a monocyclic aryl; R¹ is —H, —NR⁴R⁵,optionally substituted alkylNR⁴R⁵, —C(O)NR⁴R⁵, or —CO₂H; R³ isoptionally substituted alkyl, halo, or —S(O)₂R⁷; and R⁴ and R⁵ are eachindependently —H, optionally substituted alkyl, or —C(O)OR⁶. In someembodiments, ring A is a monocyclic aryl; R¹ is —H, or —NR⁴R⁵; R³ isoptionally substituted alkyl, halo, or —S(O)₂R⁷. In some embodiments,ring A is phenyl; R¹ is —H, or —NR⁴R⁵; R³ is optionally substitutedalkyl, or halo, and R⁴ and R⁵ are each independently —H, optionallysubstituted alkyl. In some embodiments, ring A is phenyl; R¹ is —H, or—NR⁴R⁵; R³ is alkyl; and R⁴ and R⁵ are each independently alkyl. In someembodiments, ring A is phenyl; R¹ is —NR⁴R⁵ and R³ is alkyl; and R⁴ andR⁵ are each independently alkyl. In some embodiments, ring A is phenyl;R¹ is —NR⁴R⁵ and R³ is C₁₋₆ alkyl; and R⁴ and R⁵ are each independentlyalkyl. In some embodiments, ring A is pyridyl; R¹ is —H, or —NR⁴R⁵; R³is alkyl, or halo; and R⁴ and R⁵ are each independently alkyl. In someembodiments, ring A is phenyl; R¹ is —NR⁴R⁵; R³ is alkyl; and R⁴ and R⁵are each independently alkyl. In some embodiments, ring A is pyridyl; R¹is —H, or —NR⁴R⁵; R³ is alkyl; and R⁴ and R⁵ are each independentlyalkyl. In some embodiments, ring A is pyridyl; R¹ is —NR⁴R⁵ and R³ isalkyl; and R⁴ and R⁵ are each independently alkyl. In some embodiments,ring A is pyridyl; R¹ is —NR⁴R⁵ and R³ is C₁₋₆ alkyl; and R⁴ and R⁵ areeach independently alkyl.

In some embodiments, ring A is a bicyclic aryl; R¹ is —H, —NR⁴R⁵,optionally substituted alkylNR⁴R⁵, —C(O)NR⁴R⁵, or —CO₂H; R³ isoptionally substituted alkyl, halo, or —S(O)₂R⁷; and R⁴ and R⁵ are eachindependently —H, optionally substituted alkyl, or —C(O)OR⁶. In someembodiments, ring A is a bicyclic aryl; R¹ is —H, or —NR⁴R⁵; R³ isoptionally substituted alkyl, halo, or —S(O)₂R⁷.

In some embodiments, ring A is benzo-1,4-dioxane; R¹ is —H, or —NR⁴R⁵;R³ is optionally substituted alkyl, or halo. In some embodiments, ring Ais benzo-1,4-dioxane; R¹ is —H, or —NR⁴R⁵; R³ is optionally substitutedalkyl. In some embodiments, ring A is benzo-1,4-dioxane; R¹ is —NR⁴R⁵and R³ is alkyl. In some embodiments, ring A is benzo-1,4-dioxane; R¹ is—NR⁴R⁵ and R³ is C₁₋₆ alkyl.

In some embodiments, R¹⁴ is hydrogen; each R¹³ is independently H,optionally substituted alkyl, haloalkyl, optionally substitutedcarbocyclyl, or optionally substituted heteroaryl; and n is 0, 1, 2, 3,or 4. In some embodiments, R¹⁴ is hydrogen; each R¹³ is independently H,optionally substituted alkyl, haloalkyl, or optionally substitutedheteroaryl; and n is 0, 1, or 2. In some embodiments, R¹⁴ is methyl;each R¹³ is independently H, optionally substituted alkyl, haloalkyl,optionally substituted carbocyclyl, or optionally substitutedheteroaryl; and n is 0, 1, 2, 3, or 4. In some embodiments, R¹⁴ ismethyl; each R¹³ is independently H, optionally substituted alkyl,haloalkyl, or optionally substituted heteroaryl; and n is 0, 1, or 2.

Any combination of the groups described above for the various variablesis contemplated herein. Throughout the specification, groups andsubstituents thereof are chosen by one skilled in the field to providestable moieties and compounds.

In some embodiments, compounds described herein have the followingstructure of Formula (IIa):

In some embodiments, compounds described herein have the followingstructure of Formula (IIb):

In some embodiments, compounds described herein have the followingstructure of Formula (IIc):

In some embodiments, compounds described herein have the followingstructure of Formula (IId):

In some embodiments, compounds described herein have the followingstructure of Formula (IIe):

In some embodiments, compounds described herein have the followingstructure of Formula (IIf):

In some embodiments, compounds described herein have the followingstructure of Formula (IIg):

In some embodiments, compounds described herein have the followingstructure of Formula (IIh):

Some embodiments provided herein describe a compound having thestructure of Formula (III), or a pharmaceutically acceptable salt,solvate, or prodrug thereof:

-   wherein-   ring A is a heteroaryl, aryl, cycloalkyl, or heterocyclyl;-   R¹ is —NR^(4a)R^(5a);-   each R² is independently —NR⁴R⁵, optionally substituted alkylNR⁴R⁵,    halo, —OR⁶, —OH, optionally substituted alkyl, haloalkyl, optionally    substituted carbocyclyl, optionally substituted carbocyclylalkyl,    optionally substituted heteroalkyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, optionally    substituted hydroxyalkyl, —C(O)R⁶, —C(O)OR⁶, —C(O)NR⁴R⁵, —OC(O)OR⁶,    —OC(O)NR⁴R⁵, —S(O)₂NR⁴R⁵, —S(O)₂R⁷, —S(O)R⁷, —SR⁷, —NR⁴S(O)₂NR⁴R⁵,    —CN, —CO₂H, or —NO₂;-   or R¹ and R² on adjacent atoms are taken together with the atoms to    which they are attached to form an optionally substituted    heterocycle;-   R³ is optionally substituted C₂₋₈ alkyl, halo, haloalkyl, optionally    substituted carbocyclyl, optionally substituted carbocyclylalkyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heteroalkyl, optionally    substituted aryl, optionally substituted heteroaryl, —Si(R⁶)₃, —OR⁶,    or —S(O)₂R⁷;-   R^(4a) is C₂₋₈ alkyl, optionally substituted carbocyclyl, optionally    substituted aryl, optionally substituted heterocyclyl, optionally    substituted heteroaryl, —S(O)₂R⁷, —C(O)N(R¹³)₂, —C(O)R⁶, or    —C(O)OR⁶;-   R^(5a) is —H, optionally substituted alkyl, haloalkyl, optionally    substituted carbocyclyl, optionally substituted aryl, optionally    substituted heterocyclyl, optionally substituted heteroaryl,    —S(O)₂R⁷, —C(O)N(R¹³)₂, —(O)R⁶, or —C(O)OR⁶;-   or R^(4a) and R^(5a) are taken together with the N atom to which    they are attached to form an optionally substituted heterocycle;-   R⁴ and R⁵ are each independently —H, optionally substituted alkyl,    haloalkyl, optionally substituted carbocyclyl, optionally    substituted aryl, optionally substituted heterocyclyl, optionally    substituted heteroaryl, —S(O)₂R⁷, —C(O)N(R¹³)₂, —C(O)R⁶, or    —C(O)OR⁶;-   or R⁴ and R⁵ are taken together with the N atom to which they are    attached to form an optionally substituted heterocycle;-   each R⁶ is independently optionally substituted alkyl, haloalkyl,    optionally substituted carbocyclyl, optionally substituted aryl,    optionally substituted heterocyclyl, or optionally substituted    heteroaryl;-   R⁷ is optionally substituted alkyl, haloalkyl, optionally    substituted carbocyclyl, optionally substituted heteroalkyl,    optionally substituted aryl, optionally substituted aralkyl,    optionally substituted heterocyclyl, or optionally substituted    heteroaryl;-   R⁸ and R⁹ are each independently —H, optionally substituted alkyl,    haloalkyl, halo, optionally substituted carbocyclyl, optionally    substituted carbocyclylalkyl, optionally substituted heteroalkyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, —OH, —S(O)₂R⁷, —C(O)₂H, —(O)R⁶, or —C(O)OR⁶;-   or R⁸ and R⁹ are taken together with the atom to which they are    attached to form an optionally substituted ring containing 0-2    heteroatoms selected from the group consisting of —O—, —NH—, —NR⁶—,    —S—, and —S(O)₂—;-   R¹⁰ and R¹¹ are each independently —H, optionally substituted alkyl,    halo, haloalkyl, optionally substituted carbocyclyl, optionally    substituted carbocyclylalkyl, optionally substituted heteroalkyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, —OH, —S(O)₂R⁷, —C(O)₂H, —C(O)R⁶, or —C(O)OR⁶;-   or R¹⁰ and R¹¹ an taken together with the atom to which they are    attached to form an optionally substituted ring containing 0-2    heteroatoms selected from the group consisting of —O—, —NH—, —NR⁶—,    —S—, and —S(O)₂—;-   R¹² is hydrogen, optionally substituted alkyl, haloalkyl, hydroxy,    halo, optionally substituted carbocyclyl, optionally substituted    carbocyclylalkyl, optionally substituted heterocyclyl, optionally    substituted heterocyclylalkyl, or optionally substituted    heteroalkyl;-   each R¹³ is independently H, optionally substituted alkyl,    haloalkyl, optionally substituted carbocyclyl, optionally    substituted heteroalkyl, optionally substituted aryl, optionally    substituted aralkyl, optionally substituted heterocyclyl, or    optionally substituted heteroaryl; and-   n is 0, 1, 2, 3, or 4.

In some embodiments of a compound of Formula (III):

-   ring A is aryl;-   R¹ is —NR^(4a)R^(5a);-   each R² is independently —NR⁴R⁵, halo, or optionally substituted    alkyl;-   or R¹ and R² on adjacent atoms are taken together with the atoms to    which they are attached to form an optionally substituted    heterocycle;-   R³ is optionally substituted C₂₋₈ alkyl, haloalkyl, or optionally    substituted carbocyclyl;-   R^(4a) is C₂₋₈ alkyl;-   R^(5a) is —H or optionally substituted alkyl;-   or R^(4a) and R^(5a) are taken together with the N atom to which    they are attached to form an optionally substituted heterocycle;-   R⁴ and R⁵ are each independently —H or optionally substituted alkyl;-   or R⁴ and R⁵ are taken together with the N atom to which they are    attached to form an optionally substituted heterocycle;-   R⁸ and R⁹ are each independently —H or optionally substituted alkyl;-   or R⁸ and R⁹ are taken together with the atom to which they are    attached to form an optionally substituted ring containing 0-2    heteroatoms selected from the group consisting of —O—, —NH—, —S—,    and —S(O)₂—;-   R¹⁰ and R¹¹ are each independently —H or optionally substituted    alkyl;-   or R¹⁰ and R¹¹ are taken together with the atom to which they are    attached to form an optionally substituted ring containing 0-2    heteroatoms selected from the group consisting of —O—, —NH—, —S—,    and —S(O)₂—;-   R¹² is hydrogen or optionally substituted alkyl; and-   n is 0 or 1.

In some embodiments of a compound of Formula (III):

-   ring A is aryl;-   R¹ is —NR^(4a)R^(5a);-   each R² is independently halo or alkyl;-   or R¹ and R² on adjacent atoms are taken together with the atoms to    which they are attached to form an optionally substituted    heterocycle;-   R³ is C₂₋₈ alkyl, haloalkyl, or carbocyclyl;-   R^(4a) is C₃₋₆ alkyl;-   R^(5a) is —H or C₁₋₆ alkyl;-   or R^(4a) and R^(5a) are taken together with the N atom to which    they are attached to form an optionally substituted heterocycle;-   R⁸ and R⁹ are each independently —H or methyl;-   R¹⁰ and R¹¹ are each —H;-   R¹² is hydrogen or methyl; and-   n is 0 or 1.

For any and all of the embodiments of Formula (III), substituents areselected from among a subset of the listed alternatives.

In some embodiments, ring A is monocyclic aryl, bicyclic aryl,monocyclic heteroaryl, or bicyclic heteroaryl. In some embodiments, ringA is monocyclic heteroaryl or monocyclic aryl. In some embodiments, ringA is bicyclic heteroaryl or bicyclic aryl. In some embodiments, ring Ais N-bound heteroaryl. In some embodiments, ring A is C-boundheteroaryl. In some embodiments, ring A is aryl.

In certain embodiments, ring A is phenyl, naphthyl, furanyl, pyrrolyl,oxazolyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl,isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl,pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, quinolinyl,isoquinolinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, indolyl,indazolyl, benzoxazolyl, benzisoxazolyl, benzofuranyl, benzothienyl,benzothiazolyl, benzimidazolyl, purinyl, cinnolinyl, phthalazinyl,pteridinyl, pyridopyrimidinyl, pyrazolopyrimidinyl, or azaindolyl. Insome embodiments, R¹ is furanyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl,oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl,pyridazinyl, or triazinyl. In some embodiments, ring A is pyrimidinyl,pyridinyl, pyrimidinyl, triazinyl, or thiazolyl. In certain embodiments,ring A is C-bound imidazolyl. In certain embodiments, ring A is N-boundimidazolyl. In some embodiments, ring A is pyrimidinyl. In someembodiments, ring A is pyrimidinyl optionally substituted with alkyl oralkoxy. In some embodiments, ring A is pyrazinyl. In some embodiments,ring A is triazinyl. In some embodiments, ring A is thiazolyl.

In some embodiments, ring A is phenyl, pyridinyl, pyrimidinyl,pyrazinyl, or pyridazinyl. In some embodiments, ring A is phenyl orpyridinyl. In some embodiments, ring A is phenyl.

In some embodiments, R¹ is —NR^(4a)R^(5a), R^(4a) is C₂₋₈ alkyl, andR^(5a) is —H, optionally substituted alkyl, haloalkyl, optionallysubstituted carbocyclyl, optionally substituted aryl, optionallysubstituted heterocyclyl, optionally substituted heteroaryl, —S(O)₂R⁷,—C(O)N(R¹³)₂, —C(O)R⁶, or —C(O)OR⁶. In some embodiments, R¹ isNR^(4a)R^(5a), R^(4a) is C₂₋₈ alkyl, and R^(5a) is —H or optionallysubstituted alkyl. In some embodiments, R¹ is —NR^(4a)R^(5a), R^(4a) isC₂₋₈ alkyl, and R^(5a) is —H or alkyl. In some embodiments, R¹ is—NR^(4a)R^(5a), R^(4a) is C₂₋₈ alkyl, and R^(5a) is —H or C₁₋₆ alkyl. Insome embodiments, R¹ is NR^(4a)R^(5a), R^(4a) is ethyl, i-propyl, ort-butyl, and R^(5a) is —H or C₁₋₆ alkyl. In some embodiments, R¹ is—NR^(4a)R^(5a), R^(4a) is ethyl, i-propyl, or t-butyl, and R^(5a) isC₁₋₆ alkyl.

In some embodiments, R¹ is —NR^(4a)R^(5a), R^(4a) is C₃₋₆ alkyl, andR^(5a) is —H, optionally substituted alkyl, haloalkyl, optionallysubstituted carbocyclyl, optionally substituted aryl, optionallysubstituted heterocyclyl, optionally substituted heteroaryl, —S(O)₂R⁷,—C(O)N(R¹³)₂, —C(O)R⁶, or —C(O)OR⁶. In some embodiments, R¹ is—NR^(4a)R^(5a), R^(4a) is C₃₋₆ alkyl, and R^(5a) is —H or optionallysubstituted alkyl. In some embodiments, R¹ is —NR^(4a)R^(5a), R^(4a) isC₃₋₆ alkyl, and R^(5a) is —H or alkyl. In some embodiments, R¹ is—NR^(4a)R^(5a), R^(4a) is C₃₋₆ alkyl, and R^(5a) is —H or C₁₋₆ alkyl. Insome embodiments, R¹ is —NR^(4a)R^(5a), R^(4a) is i-propyl or t-butyl,and R^(5a) is —H or C₁₋₆ alkyl. In some embodiments, R¹ is—NR^(4a)R^(5a), R^(4a) is i-propyl or t-butyl, and R^(5a) is C₁₋₆ alkyl.

In some embodiments, R¹ is —NR^(4a)R^(5a), R^(4a) is C₂₋₄ alkyl, andR^(5a) is —H, optionally substituted alkyl, haloalkyl, optionallysubstituted carbocyclyl, optionally substituted aryl, optionallysubstituted heterocyclyl, optionally substituted heteroaryl, —S(O)R⁷,—C(O)N(R¹³)₂, —C(O)R⁶, or —C(O)OR⁶. In some embodiments, R¹ is—NR^(4a)R^(5a), R^(4a) is C₂₋₄ alkyl, and R^(5a) is —H or optionallysubstituted alkyl. In some embodiments, R¹ is —NR^(4a)R^(5a), R^(4a) isC₂₋₄ alkyl, and R^(5a) is —H or alkyl. In some embodiments, R¹ is—NR^(4a)R^(5a), R^(4a) is C₂₋₄ alkyl, and R^(5a) is —H or C₁₋₆ alkyl. Insome embodiments, R¹ is —NR^(4a)R^(5a), R^(4a) is ethyl, i-propyl, ort-butyl, and R^(5a) is —H or C₁₋₆ alkyl. In some embodiments, R¹ is—NR^(4a)R^(5a), R^(4a) is ethyl, i-propyl, or t-butyl, and R^(5a) isC₁₋₆ alkyl.

In some embodiments, R¹ is —NMeEt. In some embodiments, R¹ is —NEt₂. Insome embodiments, R¹ is —NMeiPr. In some embodiments, R¹ is —NHEt. Insome embodiment, R¹ is —NHiPr.

In some embodiments, R¹ is —NR^(4a)R^(5a) and R^(4a) and R^(5a) aretaken together with the N atom to which they are attached to form anoptionally substituted heterocycle. In other embodiments, R¹ is—NR^(4a)R^(5a) and R^(4a) and R^(5a) are taken together with the N atomto which they are attached to form an optionally substituted 4-, 5-, or6-membered ring heterocycle additionally containing 0-3 heteroatomsselected from —O—, —NH—, —NR⁶—, —S—, and —S(O)₂—. In some embodiments,R¹ is —NR^(4a)R^(5a) and R^(4a) and R^(5a) are taken together with the Natom to which they are attached to form an optionally substituted 4-, 5-or 6-membered heterocycle additionally containing 0 or 1 oxygenheteroatom. In other embodiments, R¹ is —NR^(4a)R^(5a) and R^(4a) andR^(5a) are taken together with the N atom to which they are attached toform an optionally substituted 4-, 5-, or 6-membered ring heterocycleadditionally containing 1 heteroatom selected from —O—, —NH—, —NR⁶—,—S—, and —S(O)₂—. In other embodiments, R¹ is —NR^(4a)R^(5a) and R^(4a)and R^(5a) are taken together with the N atom to which they are attachedto form a 4-, 5-, or 6-membered ring. In other embodiments, R¹ is—NR^(4a)R^(5a) and R^(4a) and R^(5a) are taken together with the N atomto which they are attached to form

In other embodiments, R¹ is —NR^(4a)R^(5a) and R^(4a) and R^(5a) aretaken together with the N atom to which they are attached to form anoptionally substituted pyrrolidinyl, an optionally substitutedmorpholinyl, an optionally substituted thiomorpholinyl an optionallysubstituted piperidinyl, or an optionally substituted piperazinyl.

In some embodiments, n is 0, 1, or 2. In some embodiments, n is 0 or 1.In some embodiments, n is 1 or 2. In some embodiments, n is 3 or 4. Insome embodiments, n is 0. In some embodiments, n is 1. In someembodiments, n is 2. In some embodiments, n is 3.

In some embodiments, each R² is independently —NR⁴R⁵, optionallysubstituted alkylNR⁴R⁵, halo, —OR⁶, —OH, optionally substituted alkyl,haloalkyl, optionally substituted carbocyclyl, optionally substitutedcarbocyclylalkyl, optionally substituted heteroalkyl, optionallysubstituted heterocyclyl, optionally substituted heterocyclylalkyl,optionally substituted hydroxyalkyl, —C(O)R⁶, —C(O)NR⁴R⁵, —S(O)₂NR⁴R⁵,—S(O)₂R⁷, —NR⁴S(O)₂NR⁴R⁵, or —CN. In some embodiments, each R² isindependently —NR⁴R⁵, alkylNR⁴R⁵, halo, —OR⁶, —OH, alkyl, haloalkyl,carbocyclyl, carbocyclylalkyl, heteroalkyl, heterocyclyl,heterocyclylalkyl, hydroxyalkyl, —C(O)R⁶, —C(O)NR⁴R⁵, —S(O)₂NR⁴R⁵,—S(O)₂R⁷, —NR⁴S(O)₂NR⁴R⁵, or —CN. In some embodiments, —NR⁴R⁵, halo,—OR⁶, optionally substituted alkyl, fluoroalkyl, optionally substitutedcarbocyclyl, optionally substituted heteroalkyl, optionally substitutedheterocyclyl, —C(O)NR⁴R⁵, —S(O)₂NR⁴R⁵, —S(O)₂R⁷, —NR⁴S(O)₂NR⁴R⁵, —CN, or—CO₂H. In certain embodiments, each R² is independently —NR⁴R⁵, halo,—OR⁶, —OH, optionally substituted alkyl, fluoroalkyl, optionallysubstituted carbocyclyl, optionally substituted heteroalkyl, optionallysubstituted heterocyclyl, optionally substituted hydroxyalkyl,—S(O)₂NR⁴R⁵, —S(O)₂R⁷, —NR⁴S(O)₂NR⁴R⁵, or —CN. In some embodiments, eachR² is independently —NR⁴R⁵, halo, —OR⁶, alkyl, fluoroalkyl, carbocyclyl,heteroalkyl, heterocyclyl, —S(O)₂NR⁴R⁵, —NR⁴S(O)₂NR⁴R⁵, or —S(O)₂R⁷. Insome embodiments, each R² is independently —NR⁴R⁵, C₁₋₆ alkylNR⁴R⁵,halo, —OR⁶, —OH, C₁₋₆ alkyl, C₁₋₆ fluoroalkyl, C₃₋₆ carbocyclyl, C₁₋₆alkylC₃₋₆ carbocyclyl, C₁₋₆ heteroalkyl, C₃₋₆ heterocyclyl, C₁₋₆alkylC₃₋₆ heterocyclyl, C₁₋₆ hydroxyalkyl, or —CN. In some embodiments,each R² is independently —C(O)R⁶, —C(O)NR⁴R⁵, —S(O)₂NR⁴R⁵, —S(O)₂R⁷, or—CN. In some embodiments, each R² is independently —NR⁴R⁵, halo, —OR⁶,C₁₋₆ alkyl, C₁₋₆ fluoroalkyl, C₃₋₆ carbocyclyl, C₁₋₆ heteroalkyl, C₃₋₆heterocyclyl, or —CN. In some embodiments, each R² is independently—NR⁴R⁵, halo, alkyl, carbocyclyl, alkoxy, or —CN. In some embodiments,each R² is independently —NR⁴R⁵, halo, alkyl, or alkoxy. In someembodiments, each R² is independently methyl, methoxy, ethyl, propyl,iso-propyl, cyclopropyl, fluoro, chloro, or —NMe₂. In some embodiments,each R² is independently methyl, methoxy, iso-propyl, cyclopropyl,fluoro, chloro, or —NMe₂. In some embodiments, R² is methoxy. In someembodiments, R² is methyl. In some embodiments R² is ethyl. In someembodiments, R² is iso-propyl. In some embodiments, R² is propyl. Insome embodiments, R² is cyclopropyl. In some embodiments, R² iscyclobutyl. In some embodiments, R² is fluoro. In some embodiments, R²is chloro.

In certain embodiments, each R² is independently optionally substitutedwith halo, alkyl, hydroxy, alkoxy, or fluoroalkyl. In some embodiments,each R² is independently optionally substituted with fluoro or C₁₋₆alkyl. In some embodiments, each R² is independently optionallysubstituted with fluoro or methyl.

In some embodiments, R¹ and R² on adjacent atoms are taken together withthe atoms to which they are attached to form an optionally substitutedheterocycle. In some embodiments, R¹ and R² on adjacent atoms are takentogether with the atoms to which they are attached to form aheterocycle. In some embodiments, R¹ and R² on adjacent atoms are takentogether with the atoms to which they are attached to form a 1,4-dioxaneor a 1,3-dioxolane.

In some embodiments, R³ is optionally substituted C₂₋₈ alkyl, halo,haloalkyl, optionally substituted carbocyclyl, optionally substitutedcarbocyclylalkyl, optionally substituted heterocyclyl, optionallysubstituted heterocyclylalkyl, optionally substituted heteroalkyl,optionally substituted aryl, optionally substituted heteroaryl,—Si(R⁶)₃, —OR⁶, or —S(O)₂R⁷. In some embodiments, R³ is C₂₋₈ alkyl,halo, haloalkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl,heterocyclylalkyl, heteroalkyl, aryl, optionally substituted heteroaryl,—Si(R⁶)₃, —OR⁶, or —S(O)₂R⁷. In some embodiments, R³ is C₂₋₈ alkyl,halo, haloalkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl,heterocyclylalkyl, or heteroalkyl. In some embodiments, R³ is C₂₋₈alkyl, halo, haloalkyl, deuteroalkyl, or carbocyclyl, wherein R³ isoptionally substituted with halo, alkyl, alkoxy, hydroxy, —NR⁴R⁵, or—S(O)₂R⁷. In some embodiments, R³ is C₂₋₈ alkyl, C₁₋₆ haloalkyl, or C₃₋₆carbocyclyl.

In some embodiments, R³ is CF₃, t-butyl, or cyclopropyl. In someembodiments, R³ is C₄₋₈ alkyl. In some embodiments, R³ is t-butyl. Insome embodiments, R³ is haloalkyl. In some embodiments, R³ is CF₃. Insome embodiments, R³ is optionally substituted carbocyclyl. In someembodiments, R³ is cyclopropyl.

In certain embodiments, R³ is optionally substituted with halo, alkyl,hydroxy, alkoxy, —NR⁴R⁵, —S(O)₂R⁷ or fluoroalkyl. In some embodiments,R³ is optionally substituted with chloro, fluoro, methyl, ethyl, propyl,iso-propyl, butyl, iso-butyl, sec-butyl, tert-butyl, hydroxy, methoxy,ethoxy, propoxy, iso-propoxy, dimethylamino, diethylamino, methylamino,amino, —S(O)₂Me, or trifluoromethyl. In certain embodiments, R³ isoptionally substituted with chloro, fluoro, methyl, hydroxy, methoxy,dimethylamino, —S(O)₂Me, or trifluoromethyl.

In some embodiments, R⁸ and R⁹ are each independently —H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, halo, C₃₋₆ carbocyclyl, C₁₋₆ alkylC₃₋₆ carbocyclyl, C₁₋₆heteroalkyl, C₃₋₆ heterocyclyl, C₁₋₆ alkylC₃₋₆ heterocyclyl, —OH, —OR⁶,—NR⁴R⁵, —C(O)NR⁴R⁵, —CN, —S(O)₂R⁷, —C(O)₂H, —C(O)R⁶, or —C(O)OR⁶ or R⁸and R⁹ are taken together with the atom to which they are attached toform a ring containing 0-2 heteroatoms selected from the groupconsisting of —O—, —NH—, —NR⁶—, —S—, and —S(O)₂—. In some embodiments,R⁸ and R⁹ are each independently —H, C₁₋₆ alkyl, halo, C₃₋₆ carbocyclyl,methoxy, ethoxy, propoxy, iso-propoxy, —NH₂, —NMe₂, —NHMe, —NEt₂,—C(O)NH₂, —C(O)NMe₂, —C(O)NHMe, or —CN. In some embodiments, R⁸ and R⁹are each independently —H, C₁₋₆ alkyl, C₁₋₆ fluoroalkyl, halo, or C₃₋₆carbocyclyl. In some embodiments, R⁸ and R⁹ are each independently —H,C₁₋₆ alkyl, or C₃₋₆ carbocyclyl. In some embodiments, R⁸ and R⁹ are eachindependently —H or C₁₋₆ alkyl. In some embodiments, R⁸ is —H and R⁹ isC₁₋₆ alkyl, C₁₋₆ fluoroalkyl, or C₃₋₆ carbocyclyl. In some embodiments,R⁸ is —H and R⁹ is alkyl. In some embodiments, R⁸ is C₁₋₆ alkyl, C₁₋₆fluoroalkyl, or C₃₋₆ carbocyclyl and R⁹ is —H. In some embodiments, R⁸is methyl and R⁹ is —H. In some embodiments, R⁸ and R⁹ are —H. In someembodiments, R⁸ and R⁹ are C₁₋₆ alkyl. In some embodiments, R⁸ and R⁹are methyl.

In other embodiments, R⁸ and R⁹ are taken together with the atom towhich they are attached to form a 3-, 4-, 5-, or 6-membered ringcontaining 0-2 heteroatoms selected from the group consisting of —O—,—NH—, —NR⁶—, —S—, and —S(O)₂—. In some embodiments, R⁸ and R⁹ are takentogether with the atom to which they are attached to form a 3-, 4-, 5-,or 6-membered carbocyclic ring.

In some embodiments, R¹⁰ and R¹¹ are each independently —H, alkyl, halo,haloalkyl, carbocyclyl, heteroalkyl, or —OH. In other embodiments, R¹⁰and R¹¹ are each independently —H, C₁₋₆ alkyl, halo, C₁₋₆ alkoxy, or—OH. In certain embodiments, R¹⁰ and R¹¹ are each independently —H orC₁₋₆ alkyl. In certain embodiments, R¹⁰ and R¹¹ are each independently—H, fluoro, chloro, methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl,sec-butyl, or tert-butyl. In certain embodiments, R¹⁰ and R¹¹ are eachindependently —H, fluoro, or methyl. In certain embodiments, R¹⁰ and R¹¹are each independently —H or methyl. In certain embodiments, R¹⁰ and R¹¹are each independently —H or fluoro. In certain embodiments, R¹⁰ and R¹¹are both —H. In certain embodiments, R¹⁰ and R¹¹ are each independently—H or methoxy. In certain embodiments, R¹⁰ and R¹¹ are eachindependently —H or —OH. In certain embodiments, R¹⁰ and R¹¹ are eachindependently —H or fluoro. In certain embodiments, R¹⁰ and R¹¹ are eachindependently —H or chloro.

In some embodiments, R¹⁰ and R¹¹ are each independently —H, alkyl, halo,haloalkyl, carbocyclyl, heteroalkyl, or —OH, wherein at least one of R¹⁰or R¹¹ is not H. In other embodiments, R¹⁰ and R¹¹ are eachindependently —H, C₁₋₆ alkyl, halo, C₁₋₆ alkoxy, or —OH, wherein atleast one of R¹⁰ or R¹¹ is not H. In certain embodiments, R¹⁰ and R¹¹are each independently —H or C₁₋₆ alkyl, wherein at least one of R¹⁰ orR¹¹ is not H. In certain embodiments, R¹⁰ and R¹¹ are each independently—H, fluoro, chloro, methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl,sec-butyl, or tert-butyl, wherein at least one of R¹⁰ or R¹¹ is not H.In certain embodiment, R¹⁰ and R¹¹ are each independently —H, fluoro, ormethyl, wherein at least one of R¹⁰ or R¹¹ is not H. In certainembodiments, R¹⁰ and R¹¹ are each independently —H or methyl, wherein atleast one of R¹⁰ or R¹¹ is not H. In certain embodiments, R¹⁰ and R¹¹are each independently —H or fluoro, wherein at least one of R¹⁰ or R¹¹is not H. In certain embodiments, R¹⁰ and R¹¹ are each independently —Hor methoxy, wherein at least one of R¹⁰ or R¹¹ is not H. In certainembodiments, R¹⁰ and R¹¹ are each independently —H or —OH, wherein atleast one of R¹⁰ or R¹¹ is not H. In certain embodiments, R¹⁰ and R¹¹are each independently —H or fluoro, wherein at least one of R¹⁰ or R¹¹is not H. In certain embodiments, R¹⁰ and R¹¹ are each independently —Hor chloro, wherein at least one of R¹⁰ or R¹¹ is not H.

In some embodiments, R¹⁰ and R¹¹ are methyl. In some embodiments, R¹⁰and R¹¹ are ethyl. In some embodiments, R¹⁰ and R¹¹ are propyl. In someembodiments, R¹⁰ and R¹¹ are fluoro. In some embodiments, R¹⁰ and R¹¹are chloro. In some embodiments, R¹⁰ and R¹¹ are bromo. In someembodiments, R¹⁰ and R¹¹ are methoxy. In some embodiments, R¹⁰ and R¹¹are ethoxy. In some embodiments, R¹⁰ and R¹¹ are —OH.

In some embodiments, R¹⁰ and R¹¹ are taken together with the atom towhich they are attached to form a 3-, 4-, 5-, or 6-membered ring. Insome embodiments, R¹⁰ and R¹¹ are taken together with the atom to whichthey are attached to form a cyclopropyl, cyclobutyl, cyclopentyl, orcyclohexyl. In some embodiments, R¹⁰ and R¹¹ are taken together with theatom to which they are attached to form a cyclopropyl.

In certain embodiments, R¹⁰ and R¹¹ are optionally substituted withhalo, alkyl, hydroxy, alkoxy, or fluoroalkyl. In some embodiments, R¹⁰and R¹¹ are optionally substituted with fluoro or C₁₋₆ alkyl. In someembodiments, R¹⁰ and R¹¹ are optionally substituted with fluoro ormethyl.

In some embodiments, R¹² is hydrogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆deuteroalkyl, C₃₋₆ carbocyclyl, C₃₋₆ carbocyclylC₁₋₆ alkyl, C₃₋₆heterocyclyl, C₃₋₆ heterocyclylC₁₋₆ alkyl. In some embodiments, R¹² ishydrogen, alkyl, haloalkyl, hydroxy, halo, carbocyclyl, or heteroalkyl.In some embodiments, R¹² is hydrogen, C₁₋₆ alkyl, C₁₋₆ fluoroalkyl,carbocyclyl, or heterocyclylalkyl. In certain embodiments, R¹² is C₁₋₆alkyl or C₁₋₆ fluoroalkyl. In some embodiments, R¹² is C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ deuteroalkyl, C₃₋₆ carbocyclyl, C₃₋₆ carbocyclylC₁₋₆alkyl, C₃₋₆ heterocyclyl, C₃₋₆ heterocyclylC₁₋₆ alkyl. In someembodiments, R¹² is alkyl, haloalkyl, hydroxy, halo, carbocyclyl, orheteroalkyl. In some embodiments, R¹² is C₁₋₆ alkyl, C₁₋₆ fluoroalkyl,carbocyclyl, or heterocyclylalkyl. In certain embodiments, R¹² is C₁₋₆alkyl or C₁₋₆ fluoroalkyl. In certain embodiments, R¹² is hydrogen. Insome embodiments, R¹² is C₁₋₆ alkyl. In some embodiments, R¹² is C₁₋₃alkyl. In some embodiments, R¹² is C₂₋₈ alkyl. In some embodiments, R¹²is C₃₋₆ alkyl. In some embodiments, R¹² is methyl. In some embodiments,R¹² is ethyl. In some embodiments, R¹² is propyl. In some embodiments,R¹² is i-propyl. In some embodiments, R¹² is t-butyl. In someembodiments, R¹² is butyl. In some embodiments, R¹² is isobutyl. In someembodiments, R¹² is sec-butyl. In some embodiments, R¹² is carbocyclyl.In some embodiments, R¹² is cyclopropyl. In some embodiments, R¹² iscyclobutyl. In some embodiments, R¹² is cyclopentyl. In someembodiments, R¹² is cyclohexyl. In some embodiments, R¹² istrifluoromethyl. In some embodiments, R¹² is hydroxyalkyl. In someembodiments, R¹² is deuteromethyl.

In certain embodiments, R¹² is optionally substituted with halo, alkyl,hydroxy, alkoxy, or fluoroalkyl. In some embodiments, R¹² is optionallysubstituted with fluoro or C₁₋₆ alkyl. In some embodiments, R¹² isoptionally substituted with fluoro or methyl.

In some embodiments, R⁴ and R⁵ are each independently —H, optionallysubstituted alkyl, fluoroalkyl, optionally substituted carbocyclyl,optionally substituted carbocyclylalkyl, optionally substitutedheterocyclyl, optionally substituted heterocyclylalkyl, —S(O)₂R⁷, or—C(O)N(R¹³)₂. In some embodiments, R⁴ and R⁵ are each independently —H,C₁₋₆ alkyl, C₁₋₆ fluoroalkyl, C₃₋₆ carbocyclyl, C₁₋₆ carbocyclylalkyl,C₂₋₆ heterocyclyl, C₁₋₆ alkylC₃₋₆ heterocyclyl, —S(O)₂R⁷, or—C(O)N(R¹³)₂. In some embodiments, R⁴ and R⁵ are each independently —H,C₁₋₆ alkyl, C₁₋₆ fluoroalkyl, C₃₋₆ carbocyclyl, C₃₋₅ heterocyclyl, or—S(O)₂R⁷. In some embodiments, R⁴ and R⁵ are each independently —H, C₁₋₆alkyl, or —S(O)₂R⁷. In some embodiments, R⁴ and R⁵ are eachindependently —H, methyl, ethyl, propyl, iso-propyl, butyl, sec-butyl,iso-butyl, tert-butyl, or —S(O)₂R⁷. In some embodiments, R⁴ and R⁵ areeach independently —H, methyl, ethyl, propyl, or iso-propyl. In someembodiments, R⁴ and R⁵ are —H. In some embodiments, R⁴ and R⁵ aremethyl. In some embodiments, R⁴ is methyl and R⁵ is ethyl. In someembodiments, R⁴ is methyl and R⁵ is propyl. In some embodiments, R⁴ ismethyl and R⁵ is iso-propyl. In some embodiments, R⁴ is H and R⁵ isiso-propyl. In some embodiments, R⁴ and R⁵ are each independently —H or—C(O)N(R¹³)₂.

In other embodiments, R⁴ and R⁵ attached to the same N atom are takentogether with the N atom to which they are attached to form anoptionally substituted 4-, 5-, or 6-membered ring heterocycleadditionally containing 0-3 heteroatoms selected from —O—, —NH—, —NR⁶—,—S—, and —S(O)₂—. In some embodiments, R⁴ and R⁵ attached to the same Natom are taken together with the N atom to which they are attached toform a 4-, 5- or 6-membered heterocycle additionally containing 0 or 1oxygen heteroatom. In other embodiments, R⁴ and R⁵ attached to the sameN atom are taken together with the N atom to which they are attached toform an optionally substituted 4-, 5-, or 6-membered ring heterocycleadditionally containing 1 heteroatoms selected from —O—, —NH—, —NR⁶—,—S—, and —S(O)₂—. In other embodiments, R⁴ and R⁵ attached to the same Natom are taken together with the N atom to which they are attached toform a 4-, 5-, or 6-membered ring heterocycle additionally containing 1oxygen heteroatom. In other embodiments, R⁴ and R⁵ attached to the sameN atom are taken together with the N atom to which they are attached toform a 4-, 5-, or 6-membered ring.

In certain embodiments, R⁴ and R⁵ are each independently optionallysubstituted with halo, alkyl, hydroxy, alkoxy, or fluoroalkyl. In someembodiments, R⁴ and R⁵ are each independently optionally substitutedwith fluoro or C₁₋₆ alkyl. In some embodiments, R⁴ and R⁵ are eachindependently optionally substituted with fluoro or methyl.

In some embodiments, R⁶ is optionally substituted alkyl, fluoroalkyl,optionally substituted aryl, optionally substituted carbocyclyl, oroptionally substituted heterocyclyl. In some embodiments, R⁶ isoptionally substituted alkyl, fluoroalkyl, optionally substitutedcarbocyclyl, or optionally substituted heterocyclyl. In someembodiments, R⁶ is alkyl, aryl, carbocyclyl, or heterocyclyl. In someembodiments, R⁶ is alkyl, carbocyclyl, or heterocyclyl. In someembodiments, R⁶ is alkyl, carbocyclyl, or fluoroalkyl. In someembodiments, R⁶ is C₁₋₆ alkyl, C₁₋₆ fluoroalkyl, C₃₋₆ carbocyclyl, orC₃₋₆ heterocyclyl. In certain embodiments, R⁶ is C₁₋₆ alkyl. In certainembodiments, R⁶ is methyl, ethyl, propyl, iso-propyl, butyl, sec-butyl,iso-butyl, or tert-butyl. In some embodiments, R⁶ is optionallysubstituted phenyl.

In some embodiments, R⁷ is alkyl, carbocyclyl, optionally substitutedaryl, optionally substituted aralkyl, or optionally substitutedheterocyclyl. In some embodiments, R⁷ is C₁₋₆ alkyl, C₃₋₆ carbocyclyl,or aryl optionally substituted with halo or alkyl. In some embodiments,R⁷ is C₁₋₆ alkyl, C₃₋₆ carbocyclyl, or phenyl optionally substitutedwith halo or alkyl. In some embodiments, R⁷ is optionally substitutedbenzyl. In some embodiments, R⁷ is C₃₋₆ carbocyclyl. In someembodiments, R⁷ is phenyl. In some embodiments, R⁷ is phenyl substitutedwith 1-4 C₁₋₆ alkyl or fluoro substituents. In some embodiments, R⁷ isphenyl substituted with a C₁₋₆ alkyl or fluoro substituent. In someembodiments, R⁷ is alkyl, carbocyclyl, aralkyl, or heterocyclyl.

In certain embodiments, R⁷ is optionally substituted with halo, alkyl,hydroxy, alkoxy, or fluoroalkyl. In some embodiments, R⁷ is optionallysubstituted with fluoro or C₁₋₆ alkyl. In some embodiments, R⁷ isoptionally substituted with fluoro or methyl.

In some embodiments, each R¹³ is independently hydrogen, optionallysubstituted alkyl, haloalkyl, optionally substituted carbocyclyl,optionally substituted heteroalkyl, optionally substituted aryl,optionally substituted aralkyl, optionally substituted heterocyclyl, oroptionally substituted heteroaryl. In some embodiments, each R¹³ isindependently hydrogen, optionally substituted alkyl, optionallysubstituted carbocyclyl, optionally substituted heteroalkyl, oroptionally substituted aryl. In some embodiments, each R¹³ isindependently optionally substituted alkyl, optionally substitutedcarbocyclyl, optionally substituted heteroalkyl, optionally substitutedaryl, or heteroaryl. In some embodiments, each R¹³ is independentlyalkyl or aryl. In some embodiments, each R¹³ is independently hydrogenor C₁₋₆ alkyl. In some embodiments, each R¹³ is independently hydrogen,methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, sec-butyl,tert-butyl, pentyl or hexyl. In some embodiments, each R¹³ isindependently hydrogen, methyl, ethyl, propyl, iso-propyl, butyl, ortert-butyl. In some embodiments, each R¹³ is independently hydrogen ormethyl. In some embodiments, R¹³ is H. In other embodiments, R¹³ isalkyl. In other embodiments, R¹³ is aryl.

Any combination of the groups described above for the various variablesis contemplated herein. Throughout the specification, groups andsubstituents thereof are chosen by one skilled in the field to providestable moieties and compounds.

In some embodiments, compounds described herein have the followingstructure of Formula (IIIa):

In some embodiments, compounds described herein have the followingstructure of Formula (IIIb):

In some embodiments, compounds described herein have the followingstructure of Formula (IIIc):

In some embodiments, compounds described herein have the followingstructure of Formula (IIId):

In some embodiments, compounds described herein have the followingstructure of Formula (IIIe):

In some embodiments, compounds described herein have the followingstructure of Formula (IIIf):

In some embodiments, compounds described herein have the followingstructure of Formula (IIIg):

In some embodiments, compounds described herein have the followingstructure of Formula (IIIh):

In some embodiments of a compound of Formula (IIIa), (IIIb), (IIIc),(IIId), (IIIe), (IIIf), (IIIg), or (IIIh):

-   ring A is aryl;-   R¹ is —NR^(4a)R^(5a);-   R² is independently —NR⁴R⁵, halo, or optionally substituted alkyl;-   or R¹ and R² on adjacent atoms are taken together with the atoms to    which they are attached to form an optionally substituted    heterocycle;-   R³ is optionally substituted C₂₋₈ alkyl, haloalkyl, or optionally    substituted carbocyclyl;-   R^(4a) is C₂₋₈ alkyl;-   R^(5a) is —H or optionally substituted alkyl;-   or R^(4a) and R^(5a) are taken together with the N atom to which    they are attached to form an optionally substituted heterocycle;-   R⁴ and R⁵ are each independently —H or optionally substituted alkyl;-   or R⁴ and R⁵ are taken together with the N atom to which they are    attached to form an optionally substituted heterocycle;-   R⁸ and R⁹ are each independently —H or optionally substituted alkyl;-   or R⁸ and R⁹ are taken together with the atom to which they are    attached to form an optionally substituted ring containing 0-2    heteroatoms selected from the group consisting of —O—, —NH—, —S—,    and —S(O)₂—;-   R¹⁰ and R¹¹ are each independently —H or optionally substituted    alkyl;-   or R¹⁰ and R¹¹ are taken together with the atom to which they are    attached to form an optionally substituted ring containing 0-2    heteroatoms selected from the group consisting of —O—, —NH—, —S—,    and —S(O)₂—; and-   R¹² is hydrogen or optionally substituted alkyl.

Some embodiments provided herein describe a compound having thestructure of Formula (IV), or a pharmaceutically acceptable salt,solvate, or prodrug thereof:

-   wherein-   ring A is a heteroaryl, aryl, cycloalkyl, or heterocyclyl;-   R¹ is —NR^(4a)R^(5a);-   each R² is independently —NR⁴R⁵, optionally substituted alkylNR⁴R⁵,    halo, —OR⁶, —OH, optionally substituted alkyl, haloalkyl, optionally    substituted carbocyclyl, optionally substituted carbocyclylalkyl,    optionally substituted heteroalkyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, optionally    substituted hydroxyalkyl, —C(O)R⁶, —C(O)OR⁶, —C(O)NR⁴R⁵, —OC(O)OR⁶,    —OC(O)NR⁴R⁵, —S(O)₂NR⁴R⁵, —S(O)₂R⁷, —S(O)R⁷, —SR⁷, —NR⁴S(O)₂NR⁴R⁵,    —CN, —CO₂H, or —NO₂;-   or R¹ and R² on adjacent atoms are taken together with the atoms to    which they are attached to form an optionally substituted    heterocycle;-   R³ is optionally substituted alkyl;-   R^(4a) is C₂₋₈ alkyl, optionally substituted carbocyclyl, optionally    substituted aryl, optionally substituted heterocyclyl, optionally    substituted heteroaryl, —S(O)₂R⁷, —C(O)N(R¹³)₂, —C(O)R⁶, or    —C(O)OR⁶;-   R^(5a) is —H, optionally substituted alkyl, haloalkyl, optionally    substituted carbocyclyl, optionally substituted aryl, optionally    substituted heterocyclyl, optionally substituted heteroaryl,    —S(O)₂R⁷, —C(O)N(R¹³)₂, —C(O)R⁶, or —C(O)OR⁶;-   R⁴ and R⁵ are each independently —H, optionally substituted alkyl,    haloalkyl, optionally substituted carbocyclyl, optionally    substituted aryl, optionally substituted heterocyclyl, optionally    substituted heteroaryl, —S(O)₂R⁷, —C(O)N(R¹³)₂, —C(O)R⁶, or    —C(O)OR⁶;-   or R⁴ and R⁵ are taken together with the N atom to which they are    attached to form an optionally substituted heterocycle;-   each R⁶ is independently optionally substituted alkyl, haloalkyl,    optionally substituted carbocyclyl, optionally substituted aryl,    optionally substituted heterocyclyl, or optionally substituted    heteroaryl;-   R⁷ is optionally substituted alkyl, haloalkyl, optionally    substituted carbocyclyl, optionally substituted heteroalkyl,    optionally substituted aryl, optionally substituted aralkyl,    optionally substituted heterocyclyl, or optionally substituted    heteroaryl;-   R⁸ and R⁹ are each independently —H, optionally substituted alkyl,    haloalkyl, halo, optionally substituted carbocyclyl, optionally    substituted carbocyclylalkyl, optionally substituted heteroalkyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, —OH, —S(O)₂R⁷, —C(O)₂H, —C(O)R⁶, or —C(O)OR⁶;-   or R⁸ and R⁹ are taken together with the atom to which they are    attached to form an optionally substituted ring containing 0-2    heteroatoms selected from the group consisting of —O—, —NH—, —NR⁶—,    —S—, and —S(O)₂—;-   R¹⁰ and R¹¹ are each independently —H, optionally substituted alkyl,    halo, haloalkyl, optionally substituted carbocyclyl, optionally    substituted carbocyclylalkyl, optionally substituted heteroalkyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, —OH, —S(O)₂R⁷, —C(O)₂H, —C(O)R⁶, or —C(O)OR⁶;-   or R¹⁰ and R¹¹ are taken together with the atom to which they are    attached to form an optionally substituted ring containing 0-2    heteroatoms selected from the group consisting of —O—, —NH—, —NR⁶—,    —S—, and —S(O)₂—;-   R¹² is hydrogen, optionally substituted alkyl, haloalkyl, hydroxy,    halo, optionally substituted carbocyclyl, optionally substituted    carbocyclylalkyl, optionally substituted heterocyclyl, optionally    substituted heterocyclylalkyl, or optionally substituted    heteroalkyl;-   each R¹³ is independently H, optionally substituted alkyl,    haloalkyl, optionally substituted carbocyclyl, optionally    substituted heteroalkyl, optionally substituted aryl, optionally    substituted aralkyl, optionally substituted heterocyclyl, or    optionally substituted heteroaryl; and-   n is 0, 1, 2, 3, or 4.

In some embodiments of a compound of Formula (IV):

-   ring A is aryl;-   R¹ is —NR^(4a)R^(5a);-   R² is independently —NR⁴R⁵, halo, or optionally substituted alkyl;-   or R¹ and R² on adjacent atoms are taken together with the atoms to    which they are attached to form an optionally substituted    heterocycle;-   R³ is optionally substituted alkyl;-   R^(4a) is C₂₋₈ alkyl;-   R^(5a) is —H or optionally substituted alkyl;-   R⁴ and R⁵ are each independently —H or optionally substituted alkyl;-   or R⁴ and R⁵ are taken together with the N atom to which they are    attached to form an optionally substituted heterocycle;-   R⁸ and R⁹ are each independently —H or optionally substituted alkyl;-   or R⁸ and R⁹ are taken together with the atom to which they are    attached to form an optionally substituted ring containing 0-2    heteroatoms selected from the group consisting of —O—, —NH—, —S—,    and —S(O)₂—;-   R¹⁰ and R¹¹ are each independently —H or optionally substituted    alkyl;-   or R¹⁰ and R¹¹ are taken together with the atom to which they are    attached to form an optionally substituted ring containing 0-2    heteroatoms selected from the group consisting of —O—, —NH—, —S—,    and —S(O)₂—; and-   R¹² is hydrogen or optionally substituted alkyl.

Some embodiments provided herein describe a compound having thestructure of Formula (V), or a pharmaceutically acceptable salt,solvate, or prodrug thereof:

-   wherein-   ring A is a heteroaryl, aryl, cycloalkyl, or heterocyclyl;-   R¹ is —NR^(4a)R^(5a), optionally substituted alkylNR⁴R⁵, halo, —OR⁶,    —OH, optionally substituted alkyl, haloalkyl, optionally substituted    carbocyclyl, optionally substituted carbocyclylalkyl, optionally    substituted heteroalkyl, optionally substituted heterocyclyl,    optionally substituted heterocyclylalkyl, optionally substituted    hydroxyalkyl, —C(O)R⁶, —C(O)OR⁶, —C(O)NR⁴R⁵, —OC(O)OR⁶, —OC(O)NR⁴R⁵,    —S(O)₂NR⁴R⁵, —S(O)₂R⁷, —S(O)R⁷, —SR⁷, —NR⁴S(O)₂NR⁴R⁵, —CN, —CO₂H, or    —NO₂;-   each R² is independently —NR⁴R⁵, optionally substituted alkylNR⁴R⁵,    halo, —OR⁶, —OH, optionally substituted alkyl, haloalkyl, optionally    substituted carbocyclyl, optionally substituted carbocyclylalkyl,    optionally substituted heteroalkyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, optionally    substituted hydroxyalkyl, —C(O)R⁶, —C(O)OR⁶, —C(O)NR⁴R⁵, —OC(O)OR⁶,    —OC(O)NR⁴R⁵, —S(O)₂NR⁴R⁵, —S(O)₂R⁷, —S(O)R⁷, —SR⁷, —NR⁴S(O)₂NR⁴R⁵,    —CN, —CO₂H or —NO₂;-   or R¹ and R² on adjacent atoms are taken together with the atoms to    which they are attached to form an optionally substituted    heterocycle;-   R³ is optionally substituted carbocyclyl;-   R⁴ is optionally substituted alkyl, optionally substituted    carbocyclyl, optionally substituted aryl, optionally substituted    heterocyclyl, optionally substituted heteroaryl, —S(O)₂R⁷,    —C(O)N(R¹³)₂, —C(O)R⁶, or —C(O)OR⁶;-   R^(5a) is —H, optionally substituted alkyl, haloalkyl, optionally    substituted carbocyclyl, optionally substituted aryl, optionally    substituted heterocyclyl, optionally substituted heteroaryl,    —S(O)₂R⁷, —C(O)N(R¹³)₂, —C(O)R⁶, or —C(O)OR⁶;-   or R^(4a) and R^(5a) are taken together with the N atom to which    they are attached to form an optionally substituted heterocycle;-   R⁴ and R⁵ are each independently —H, optionally substituted alkyl,    haloalkyl, optionally substituted carbocyclyl, optionally    substituted aryl, optionally substituted heterocyclyl, optionally    substituted heteroaryl, —S(O)₂R⁷, —C(O)N(R¹³)₂, —C(O)R⁶, or    —C(O)OR⁶;-   or R⁴ and R⁵ are taken together with the N atom to which they are    attached to form an optionally substituted heterocycle;-   each R⁶ is independently optionally substituted alkyl, haloalkyl,    optionally substituted carbocyclyl, optionally substituted aryl,    optionally substituted heterocyclyl, or optionally substituted    heteroaryl;-   R⁷ is optionally substituted alkyl, haloalkyl, optionally    substituted carbocyclyl, optionally substituted heteroalkyl,    optionally substituted aryl, optionally substituted aralkyl,    optionally substituted heterocyclyl, or optionally substituted    heteroaryl;-   R⁸ and R⁹ are each independently —H, optionally substituted alkyl,    haloalkyl, halo, optionally substituted carbocyclyl, optionally    substituted carbocyclylalkyl, optionally substituted heteroalkyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, —OH, —S(O)₂R⁷, —C(O)₂H, —C(O)R⁶, or —C(O)OR⁶;-   or R⁸ and R⁹ are taken together with the atom to which they are    attached to form an optionally substituted ring containing 0-2    heteroatoms selected from the group consisting of —O—, —NH—, —NR⁶—,    —S—, and —S(O)₂—;-   R¹⁰ and R¹¹ are each independently —H, optionally substituted alkyl,    halo, haloalkyl, optionally substituted carbocyclyl, optionally    substituted carbocyclylalkyl, optionally substituted heteroalkyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, —OH, —S(O)₂R⁷, —C(O)₂, —C(O)R⁶, or —C(O)OR⁶;-   or R¹⁰ and R¹¹ are taken together with the atom to which they are    attached to form an optionally substituted ring containing 0-2    heteroatoms selected from the group consisting of —O—, —NH—, —NR⁶—,    —S—, and —S(O)₂—;-   R¹² is hydrogen;-   each R¹³ is independently H, optionally substituted alkyl,    haloalkyl, optionally substituted carbocyclyl, optionally    substituted heteroalkyl, optionally substituted aryl, optionally    substituted aralkyl, optionally substituted heterocyclyl, or    optionally substituted heteroaryl; and-   n is 0, 1, 2, 3, or 4.

In some embodiments of a compound of Formula (V):

-   ring A is aryl;-   R¹ is —NR^(4a)R^(5a);-   each R² is independently —NR⁴R⁵, halo, or optionally substituted    alkyl;-   or R¹ and R² on adjacent atoms are taken together with the atoms to    which they are attached to form an optionally substituted    heterocycle;-   R³ is optionally substituted carbocyclyl;-   R^(4a) is optionally substituted alkyl;-   R^(5a) is —H or optionally substituted alkyl;-   or R^(4a) and R^(5a) are taken together with the N atom to which    they are attached to form an optionally substituted heterocycle;-   R⁴ and R⁵ are each independently —H or optionally substituted alkyl;-   or R⁴ and R⁵ are taken together with the N atom to which they are    attached to form an optionally substituted heterocycle;-   R⁸ and R⁹ are each independently —H or optionally substituted alkyl;-   or R⁸ and R⁹ are taken together with the atom to which they are    attached to form an optionally substituted ring containing 0-2    heteroatoms selected from the group consisting of —O—, —NH—, —S—,    and —S(O)₂—;-   R¹⁰ and R¹¹ are each independently —H or optionally substituted    alkyl;-   or R¹⁰ and R¹¹ are taken together with the atom to which they are    attached to form an optionally substituted ring containing 0-2    heteroatoms selected from the group consisting of —O—, —NH—, —S—,    and —S(O)₂—;-   R¹² is hydrogen; and-   n is 0 or 1.

For any and all of the embodiments of Formulas (IV) and (V),substituents are selected from among a subset of the listedalternatives.

In some embodiments, ring A is monocyclic aryl, bicyclic aryl,monocyclic heteroaryl, or bicyclic heteroaryl. In some embodiments, ringA is monocyclic heteroaryl or monocyclic aryl. In some embodiments, ringA is bicyclic heteroaryl or bicyclic aryl. In some embodiments, ring Ais N-bound heteroaryl. In some embodiments, ring A is C-boundheteroaryl. In some embodiments, ring A is aryl.

In certain embodiments, ring A is phenyl, naphthyl, furanyl, pyrrolyl,oxazolyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl,isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl,pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, quinolinyl,isoquinolinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, indolyl,indazolyl, benzoxazolyl, benzisoxazolyl, benzofuranyl, benzothienyl,benzothiazolyl, benzimidazolyl, purinyl, cinnolinyl, phthalazinyl,pteridinyl, pyridopyrimidinyl, pyrazolopyrimidinyl, or azaindolyl. Insome embodiments, R¹ is furanyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl,oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl,pyridazinyl, or triazinyl. In some embodiments, ring A is pyrimidinyl,pyridinyl, pyrazinyl, triazinyl, or thiazolyl. In certain embodiments,ring A is C-bound imidazolyl. In certain embodiments, ring A is N-boundimidazolyl. In some embodiments, ring A is pyrimidinyl. In someembodiments, ring A is pyrimidinyl optionally substituted with alkyl oralkoxy. In some embodiments, ring A is pyrazinyl. In some embodiments,ring A is triazinyl. In some embodiments, ring A is thiazolyl.

In some embodiments, ring A is phenyl, pyridinyl, pyrimidinyl,pyrazinyl, or pyridazinyl. In some embodiments, ring A is phenyl orpyridinyl. In some embodiments, ring A is phenyl.

In some embodiments, R¹ is —NR^(4a)R^(5a), R^(4a) is C₂₋₈ alkyl, andR^(5a) is —H, optionally substituted alkyl, haloalkyl, optionallysubstituted carbocyclyl, optionally substituted aryl, optionallysubstituted heterocyclyl, optionally substituted heteroaryl, —S(O)₂R⁷,—C(O)N(R¹³)₂, —C(O)R⁶, or —C(O)OR⁶. In some embodiments, R¹ isNR^(4a)R^(5a), R^(4a) is C₂₋₈ alkyl, and R^(5a) is —H or optionallysubstituted alkyl. In some embodiments, R¹ is —NR^(4a)R^(5a), R^(4a) isC₂₋₈ alkyl, and R^(5a) is —H or alkyl. In some embodiments, R¹ is—NR^(4a)R^(5a), R^(4a) is C₂₋₈ alkyl, and R^(5a) is —H or C₁₋₆ alkyl. Insome embodiments, R¹ is —NR^(4a)R^(5a), R^(4a) is ethyl, i-propyl, ort-butyl, and R^(5a) is —H or C₁₋₆ alkyl. In some embodiments, R¹ is—NR^(4a)R^(5a), R^(4a) is ethyl, i-propyl, or t-butyl, and R^(5a) isC₁₋₆ alkyl.

In some embodiments, R¹ is —NR^(4a)R^(5a), R^(4a) is C₃₋₆ alkyl, andR^(5a) is —H, optionally substituted alkyl, haloalkyl, optionallysubstituted carbocyclyl, optionally substituted aryl, optionallysubstituted heterocyclyl, optionally substituted heteroaryl, —S(O)₂R⁷,—C(O)N(R¹³)₂, —C(O)R⁶, or —C(O)OR⁶. In some embodiments, R¹ is—NR^(4a)R^(5a), R^(4a) is C₃₋₆ alkyl, and R^(5a) is —H or optionallysubstituted alkyl. In some embodiments, R¹ is —NR^(4a)R^(5a), R^(4a) isC₃₋₆ alkyl, and R^(5a) is —H or alkyl. In some embodiments, R¹ is—NR^(4a)R^(5a), R^(4a) is C₃₋₆ alkyl, and R^(5a) is —H or C₁₋₆ alkyl. Insome embodiments, R¹ is —NR^(4a)R^(5a), R^(4a) is i-propyl or t-butyl,and R^(5a) is —H or C₁₋₆ alkyl. In some embodiments, R¹ is—NR^(4a)R^(5a), R^(4a) is i-propyl or t-butyl, and R^(5a) is C₁₋₆ alkyl.

In some embodiments, R¹ is —NR^(4a)R^(5a), R^(4a) is C₂₋₄ alkyl, andR^(5a) is —H, optionally substituted alkyl, haloalkyl, optionallysubstituted carbocyclyl, optionally substituted aryl, optionallysubstituted heterocyclyl, optionally substituted heteroaryl, —S(O)R⁷,—C(O)N(R¹³)₂, —C(O)R⁶, or —C(O)OR⁶. In some embodiments, R¹ isNR^(4a)R^(5a), R^(4a) is C₂₋₄ alkyl, and R^(5a) is —H or optionallysubstituted alkyl. In some embodiments, R¹ is —NR^(4a)R^(5a), R^(4a) isC₂₋₄ alkyl, and R^(5a) is —H or alkyl. In some embodiments, R¹ is—NR^(4a)R^(5a), R^(4a) is C₂₋₄ alkyl, and R^(5a) is —H or C₁₋₆ alkyl. Insome embodiments, R¹ is —NR^(4a)R^(5a), R^(4a) is ethyl, i-propyl, ort-butyl, and R^(5a) is —H or C₁₋₆ alkyl. In some embodiments, R¹ is—NR^(4a)R^(5a), R^(4a) is ethyl, i-propyl, or t-butyl, and R^(5a) isC₁₋₆ alkyl.

In some embodiments, R¹ is —NMeEt. In some embodiments, R¹ is —NEt₂. Insome embodiments, R¹ is —NMeiPr. In some embodiments, R¹ is —NHEt. Insome embodiment, R¹ is —NHiPr.

In some embodiments, R¹ is —NR^(4a)R^(5a) and R^(4a) and R^(5a) aretaken together with the N atom to which they are attached to form anoptionally substituted heterocycle. In other embodiments, R¹ is—NR^(4a)R^(5a) and R^(4a) and R^(5a) are taken together with the N atomto which they are attached to form an optionally substituted 4-, 5-, or6-membered ring heterocycle additionally containing 0-3 heteroatomsselected from —O—, —NH—, —NR⁶—, —S—, and —S(O)₂—. In some embodiments,R¹ is —NR^(4a)R^(5a) and R^(4a) and R^(5a) are taken together with the Natom to which they are attached to form an optionally substituted 4-, 5-or 6-membered heterocycle additionally containing 0 or 1 oxygenheteroatom. In other embodiments, R¹ is —NR^(4a)R^(5a) and R^(4a) andR^(5a) are taken together with the N atom to which they are attached toform an optionally substituted 4-, 5-, or 6-membered ring heterocycleadditionally containing 1 heteroatom selected from —O—, —NH—, —NR⁶—,—S—, and —S(O)₂—. In other embodiments, R¹ is —NR^(4a)R^(5a) and R^(4a)and R^(5a) are taken together with the N atom to which they are attachedto form a 4-, 5-, or 6-membered ring. In other embodiments, R¹ is—NR^(4a)R^(5a) and R^(4a) and R^(5a) are taken together with the N atomto which they are attached to form

In other embodiments, R¹ is —NR^(4a)R^(5a) and R^(4a) and R^(5a) aretaken together with the N atom to which they are attached to form anoptionally substituted pyrrolidinyl, an optionally substitutedmorpholinyl, an optionally substituted thiomorpholinyl, an optionallysubstituted piperidinyl, or an optionally substituted piperazinyl.

In some embodiments, n is 0, 1, or 2. In some embodiments, n is 0 or 1.In some embodiments, n is 1 or 2. In some embodiments, n is 3 or 4. Insome embodiments, n is 0. In some embodiments, n is 1. In someembodiments, n is 2. In some embodiments, n is 3.

In some embodiments, each R² is independently —NR⁴R⁵, optionallysubstituted alkylNR⁴R⁵, halo, —OR⁶, —OH, optionally substituted alkyl,haloalkyl, optionally substituted carbocyclyl, optionally substitutedcarbocyclylalkyl, optionally substituted heteroalkyl, optionallysubstituted heterocyclyl, optionally substituted heterocyclylalkyl,optionally substituted hydroxyalkyl, —C(O)R⁶, —C(O)NR⁴R⁵, —S(O)₂NR⁴R⁵,—S(O)₂R⁷, —NR⁴S(O)₂NR⁴R⁵, or —CN. In some embodiments, each R² isindependently —NR⁴R⁵, alkylNR⁴R⁵, halo, —OR⁶, —OH, alkyl, haloalkyl,carbocyclyl, carbocyclylalkyl, heteroalkyl, heterocyclyl,heterocyclylalkyl, hydroxyalkyl, —C(O)R⁶, —C(O)NR⁴R⁵, —S(O)₂NR⁴R⁵,—S(O)₂R⁷, —NR⁴S(O)₂NR⁴R⁵, or —CN. In some embodiments, —NR⁴R⁵, halo,—OR⁶, optionally substituted alkyl, fluoroalkyl, optionally substitutedcarbocyclyl, optionally substituted heteroalkyl, optionally substitutedheterocyclyl, —C(O)NR⁴R⁵, —S(O)₂NR⁴R⁵, —S(O)₂R⁷, —NR⁴S(O)₂NR⁴R⁵, —CN, or—CO₂H. In certain embodiments, each R² is independently —NR⁴R⁵, halo,—OR⁶, —OH, optionally substituted alkyl, fluoroalkyl, optionallysubstituted carbocyclyl, optionally substituted heteroalkyl, optionallysubstituted heterocyclyl, optionally substituted hydroxyalkyl,—S(O)₂NR⁴R⁵, —S(O)₂R⁷, —NR⁴S(O)₂NR⁴R⁵, or —CN. In some embodiments, eachR² is independently —NR⁴R⁵, halo, —OR⁶, alkyl, fluoroalkyl, carbocyclyl,heteroalkyl, heterocyclyl, —S(O)₂NR⁴R⁵, —NR⁴S(O)₂NR⁴R⁵, or —S(O)₂R⁷. Insome embodiments, each R² is independently —NR⁴R⁵, C₁₋₆ alkylNR⁴R⁵,halo, —OR⁶, —OH, C₁₋₆ alkyl, C₁₋₆ fluoroalkyl, C₃₋₆ carbocyclyl, C₁₋₆alkylC₃₋₆ carbocyclyl, C₁₋₆ heteroalkyl, C₃₋₆ heterocyclyl, C₁₋₆alkylC₃₋₆ heterocyclyl, C₁₋₆ hydroxyalkyl, or —CN. In some embodiments,each R² is independently —C(O)R⁶, —C(O)NR⁴R⁵, —S(O)₂NR⁴R⁵, —S(O)₂R⁷, or—CN. In some embodiments, each R² is independently —NR⁴R⁵, halo, —OR⁶,C₁₋₆ alkyl, C₁₋₆ fluoroalkyl, C₃₋₆ carbocyclyl, C₁₋₆ heteroalkyl, C₃₋₆heterocyclyl, or —CN. In some embodiments, each R² is independently—NR⁴R⁵, halo, alkyl, carbocyclyl, alkoxy, or —CN. In some embodiments,each R² is independently —NR⁴R⁵, halo, alkyl, or alkoxy. In someembodiments, each R² is independently methyl, methoxy, ethyl, propyl,iso-propyl, cyclopropyl, fluoro, chloro, or —NMe₂. In some embodiments,each R² is independently methyl, methoxy, iso-propyl, cyclopropyl,fluoro, chloro, or —NMe₂. In some embodiments, R² is methoxy. In someembodiments, R² is methyl. In some embodiments R² is ethyl. In someembodiments, R² is iso-propyl. In some embodiments, R² is propyl. Insome embodiments, R² is cyclopropyl. In some embodiments, R² iscyclobutyl. In some embodiments, R² is fluoro. In some embodiments, R²is chloro.

In certain embodiments, each R² is independently optionally substitutedwith halo, alkyl, hydroxy, alkoxy, or fluoroalkyl. In some embodiments,each R² is independently optionally substituted with fluoro or C₁₋₆alkyl. In some embodiments, each R² is independently optionallysubstituted with fluoro or methyl.

In some embodiments, R¹ and R² on adjacent atoms are taken together withthe atoms to which they are attached to form an optionally substitutedheterocycle. In some embodiments, R¹ and R² on adjacent atoms are takentogether with the atoms to which they are attached to form aheterocycle. In some embodiments, R¹ and R² on adjacent atoms are takentogether with the atoms to which they are attached to form a 1,4-dioxaneor a 1,3-dioxolane.

In some embodiments, R³ is optionally substituted C₂₋₈ alkyl, halo,haloalkyl, optionally substituted carbocyclyl, optionally substitutedcarbocyclylalkyl, optionally substituted heterocyclyl, optionallysubstituted heterocyclylalkyl, optionally substituted heteroalkyl,optionally substituted aryl, optionally substituted heteroaryl,—Si(R⁶)₃, —OR⁶, or —S(O)R⁷. In some embodiments, R³ is C₂₋₈ alkyl, halo,haloalkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl,heterocyclylalkyl, heteroalkyl, aryl, optionally substituted heteroaryl,—Si(R⁶)₃, —OR⁶, or —S(O)₂R⁷. In some embodiments, R³ is C₂₋₈ alkyl,halo, haloalkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl,heterocyclylalkyl, or heteroalkyl. In some embodiments, R³ is C₂₋₈alkyl, halo, haloalkyl, deuteroalkyl, or carbocyclyl, wherein R³ isoptionally substituted with halo, alkyl, alkoxy, hydroxy, —NR⁴R⁵, or—S(O)₂R⁷. In some embodiments, R³ is C₂₋₈ alkyl, C₁₋₆ haloalkyl, or C₃₋₆carbocyclyl.

In some embodiments, R³ is CF₃, t-butyl, or cyclopropyl. In someembodiments, R³ is C₄₋₈ alkyl. In some embodiments, R³ is t-butyl. Insome embodiments, R³ is haloalkyl. In some embodiments, R³ is CF₃. Insome embodiments, R³ is optionally substituted carbocyclyl. In someembodiments, R³ is cyclopropyl.

In certain embodiments, R³ is optionally substituted with halo, alkyl,hydroxy, alkoxy, —NR⁴R⁵, —S(O)₂R⁷ or fluoroalkyl. In some embodiments,R³ is optionally substituted with chloro, fluoro, methyl, ethyl, propyl,iso-propyl, butyl, iso-butyl, sec-butyl, tert-butyl, hydroxy, methoxy,ethoxy, propoxy, iso-propoxy, dimethylamino, diethylamino, methylamino,amino, —S(O)₂Me, or trifluoromethyl. In certain embodiments, R³ isoptionally substituted with chloro, fluoro, methyl, hydroxy, methoxy,dimethylamino, —S(O)₂Me, or trifluoromethyl.

In some embodiments, R⁸ and R⁹ are each independently —H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, halo, C₃₋₆ carbocyclyl, C₁₋₆ alkylC₃₋₆ carbocyclyl, C₁₋₆heteroalkyl, C₃₋₆ heterocyclyl, C₁₋₆ alkylC₃₋₆ heterocyclyl, —OH, —OR⁶,—NR⁴R⁵, —C(O)NR⁴R⁵, —CN, —S(O)₂R⁷, —C(O)₂H, —C(O)R⁶, or —C(O)OR⁶ or R⁸and R⁹ are taken together with the atom to which they are attached toform a ring containing 0-2 heteroatoms selected from the groupconsisting of —O—, —NH—, —NR⁶—, —S—, and —S(O)₂—. In some embodiments,R⁸ and R⁹ are each independently —H, C₁₋₆ alkyl, halo, C₃₋₆ carbocyclyl,methoxy, ethoxy, propoxy, iso-propoxy, —NH₂, —NMe₂, —NHMe, —NEt₂,—C(O)NH₂, —C(O)NMe₂, —C(O)NHMe, or —CN. In some embodiments, R⁸ and R⁹are each independently —H, C₁₋₆ alkyl, C₁₋₆ fluoroalkyl, halo, or C₃₋₆carbocyclyl. In some embodiments, R⁸ and R⁹ are each independently —H,C₁₋₆ alkyl, or C₃₋₆ carbocyclyl. In some embodiments, R⁸ and R⁹ are eachindependently —H or C₁₋₆ alkyl. In some embodiments, R⁸ is —H and R⁹ isC₁₋₆ alkyl, C₁₋₆ fluoroalkyl, or C₃₋₆ carbocyclyl. In some embodiments,R⁸ is —H and R⁹ is alkyl. In some embodiments, R⁸ is C₁₋₆ alkyl, C₁₋₆fluoroalkyl, or C₃₋₆ carbocyclyl and R⁹ is —H. In some embodiments, R⁸is methyl and R⁹ is —H. In some embodiments, R⁸ and R⁹ are —H. In someembodiments, R⁸ and R⁹ are C₁₋₆ alkyl. In some embodiments, R⁸ and R⁹are methyl.

In other embodiments, R⁸ and R⁹ are taken together with the atom towhich they are attached to form a 3-, 4-, 5-, or 6-membered ringcontaining 0-2 heteroatoms selected from the group consisting of —O—,—NH—, —NR⁶—, —S—, and —S(O)₂—. In some embodiments, R⁸ and R⁹ are takentogether with the atom to which they are attached to form a 3-, 4-, 5-,or 6-membered carbocyclic ring.

In some embodiments, R¹⁰ and R¹¹ are each independently —H, alkyl, halo,haloalkyl, carbocyclyl, heteroalkyl, or —OH. In other embodiments, R¹⁰and R¹¹ are each independently —H, C₁₋₆ alkyl, halo, C₁₋₆ alkoxy, or—OH. In certain embodiments, R¹⁰ and R¹¹ are each independently —H orC₁₋₆ alkyl. In certain embodiments, R¹⁰ and R¹¹ are each independently—H, fluoro, chloro, methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl,sec-butyl, or tert-butyl. In certain embodiments, R¹⁰ and R¹¹ are eachindependently —H, fluoro, or methyl. In certain embodiments, R¹⁰ and R¹¹are each independently —H or methyl. In certain embodiments, R¹⁰ and R¹¹are each independently —H or fluoro. In certain embodiments, R¹⁰ and R¹¹are both —H. In certain embodiments, R¹⁰ and R¹¹ are each independently—H or methoxy. In certain embodiments, R¹⁰ and R¹¹ are eachindependently —H or —OH. In certain embodiments, R¹⁰ and R¹¹ are eachindependently —H or fluoro. In certain embodiments, R¹⁰ and R¹¹ are eachindependently —H or chloro.

In some embodiments, R¹⁰ and R¹¹ are each independently —H, alkyl, halo,haloalkyl, carbocyclyl, heteroalkyl, or —OH, wherein at least one of R¹⁰or R¹¹ is not H. In other embodiments, R¹⁰ and R¹¹ are eachindependently —H, C₁₋₆ alkyl, halo, C₁₋₆ alkoxy, or —OH, wherein atleast one of R¹⁰ or R¹¹ is not H. In certain embodiments, R¹⁰ and R¹¹are each independently —H or C₁₋₆ alkyl, wherein at least one of R¹⁰ orR¹¹ is not H. In certain embodiments, R¹⁰ and R¹¹ are each independently—H, fluoro, chloro, methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl,sec-butyl, or tert-butyl, wherein at least one of R¹⁰ or R¹¹ is not H.In certain embodiment, R¹⁰ and R¹¹ are each independently —H, fluoro, ormethyl, wherein at least one of R¹⁰ or R¹¹ is not H. In certainembodiments, R¹⁰ and R¹¹ are each independently —H or methyl, wherein atleast one of R¹⁰ or R¹¹ is not H. In certain embodiments, R¹⁰ and R¹¹are each independently —H or fluoro, wherein at least one of R¹⁰ or R¹¹is not H. In certain embodiments, R¹⁰ and R¹¹ are each independently —Hor methoxy, wherein at least one of R¹⁰ or R¹¹ is not H. In certainembodiments, R¹⁰ and R¹¹ are each independently —H or —OH, wherein atleast one of R¹⁰ or R¹¹ is not H. In certain embodiments, R¹⁰ and R¹¹are each independently —H or fluoro, wherein at least one of R¹⁰ or R¹¹is not H. In certain embodiments, R¹⁰ and R¹¹ are each independently —Hor chloro, wherein at least one of R¹⁰ or R¹¹ is not H.

In some embodiments, R¹⁰ and R¹¹ are methyl. In some embodiments, R¹⁰and R¹¹ are ethyl. In some embodiments, R¹⁰ and R¹¹ are propyl. In someembodiments, R¹⁰ and R¹¹ are fluoro. In some embodiments, R¹⁰ and R¹¹are chloro. In some embodiments, R¹⁰ and R¹¹ are bromo. In someembodiments, R¹⁰ and R¹¹ are methoxy. In some embodiments, R¹⁰ and R¹¹are ethoxy. In some embodiments, R¹⁰ and R¹¹ are —OH.

In some embodiments, R¹⁰ and R¹¹ are taken together with the atom towhich they are attached to form a 3-, 4-, 5-, or 6-membered ring. Insome embodiments, R¹⁰ and R¹¹ are taken together with the atom to whichthey are attached to form a cyclopropyl, cyclobutyl, cyclopentyl, orcyclohexyl. In some embodiments, R¹⁰ and R¹¹ are taken together with theatom to which they are attached to form a cyclopropyl.

In certain embodiments, R¹⁰ and R¹¹ are optionally substituted withhalo, alkyl, hydroxy, alkoxy, or fluoroalkyl. In some embodiments, R¹⁰and R¹¹ are optionally substituted with fluoro or C₁₋₆ alkyl. In someembodiments, R¹⁰ and R¹¹ are optionally substituted with fluoro ormethyl.

In some embodiments, R¹² is hydrogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆deuteroalkyl, C₃₋₆ carbocyclyl, C₃₋₆ carbocyclylC₁₋₆ alkyl, C₃₋₆heterocyclyl, C₃₋₆ heterocyclylC₁₋₆ alkyl. In some embodiments, R¹² ishydrogen, alkyl, haloalkyl, hydroxy, halo, carbocyclyl, or heteroalkyl.In some embodiments, R¹² is hydrogen, C₁₋₆ alkyl, C₁₋₆ fluoroalkyl,carbocyclyl, or heterocyclylalkyl. In certain embodiments, R¹² is C₁₋₆alkyl or C₁₋₆ fluoroalkyl. In some embodiments, R¹² is C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ deuteroalkyl, C₃₋₆ carbocyclyl, C₃₋₆ carbocyclylC₁₋₆alkyl, C₃₋₆ heterocyclyl, C₃₋₆ heterocyclylC₁₋₆ alkyl. In someembodiments, R¹² is alkyl, haloalkyl, hydroxy, halo, carbocyclyl, orheteroalkyl. In some embodiments, R¹² is C₁₋₆ alkyl, C₁₋₆ fluoroalkyl,carbocyclyl, or heterocyclylalkyl. In certain embodiments, R¹² is C₁₋₆alkyl or C₁₋₆ fluoroalkyl. In certain embodiments, R¹² is hydrogen. Insome embodiments, R¹² is C₁₋₆ alkyl. In some embodiments, R¹² is C₁₋₃alkyl. In some embodiments, R¹² is C₂₋₈ alkyl. In some embodiments, R¹²is C₃₋₆ alkyl. In some embodiments, R¹² is methyl. In some embodiments,R¹² is ethyl. In some embodiments, R¹² is propyl. In some embodiments,R¹² is i-propyl. In some embodiments, R¹² is t-butyl. In someembodiments, R¹² is butyl. In some embodiments, R¹² is isobutyl. In someembodiments, R¹² is sec-butyl. In some embodiments, R¹² is carbocyclyl.In some embodiments, R¹² is cyclopropyl. In some embodiments, R¹² iscyclobutyl. In some embodiments, R¹² is cyclopentyl. In someembodiments, R¹² is cyclohexyl. In some embodiments, R¹² istrifluoromethyl. In some embodiments, R¹² is hydroxyalkyl. In someembodiments, R¹² is deuteromethyl.

In certain embodiments, R¹² is optionally substituted with halo, alkyl,hydroxy, alkoxy, or fluoroalkyl. In some embodiments, R¹² is optionallysubstituted with fluoro or C₁₋₆ alkyl. In some embodiments, R¹² isoptionally substituted with fluoro or methyl.

In some embodiments, R⁴ and R⁵ are each independently —H, optionallysubstituted alkyl, fluoroalkyl, optionally substituted carbocyclyl,optionally substituted carbocyclylalkyl, optionally substitutedheterocyclyl, optionally substituted heterocyclylalkyl, —S(O)₂R⁷, or—C(O)N(R¹³)₂. In some embodiments, R⁴ and R⁵ are each independently —H,C₁₋₆ alkyl, C₁₋₆ fluoroalkyl, C₃₋₆ carbocyclyl, C₁₋₆ carbocyclylalkyl,C₂₋₆ heterocyclyl, C₁₋₆ alkylC₃₋₆ heterocyclyl, —S(O)₂R⁷, or—C(O)N(R¹³)₂. In some embodiments, R⁴ and R⁵ are each independently —H,C₁₋₆ alkyl, C₁₋₆ fluoroalkyl, C₃₋₆ carbocyclyl, C₃₋₅ heterocyclyl, or—S(O)₂R⁷. In some embodiments, R⁴ and R⁵ are each independently —H, C₁₋₆alkyl, or —S(O)₂R⁷. In some embodiments, R⁴ and R⁵ are eachindependently —H, methyl, ethyl, propyl, iso-propyl, butyl, sec-butyl,iso-butyl, tert-butyl, or —S(O)₂R⁷. In some embodiments, R⁴ and R⁵ areeach independently —H, methyl, ethyl, propyl, or iso-propyl. In someembodiments, R⁴ and R⁵ are —H. In some embodiments, R⁴ and R⁵ aremethyl. In some embodiments, R⁴ is methyl and R⁵ is ethyl. In someembodiments, R⁴ is methyl and R⁵ is propyl. In some embodiments, R⁴ ismethyl and R⁵ is iso-propyl. In some embodiments, R⁴ is H and R⁵ isiso-propyl. In some embodiments, R⁴ and R⁵ are each independently —H or—C(O)N(R¹³)₂.

In other embodiments, R⁴ and R⁵ attached to the same N atom are takentogether with the N atom to which they are attached to form anoptionally substituted 4-, 5-, or 6-membered ring heterocycleadditionally containing 0-3 heteroatoms selected from —O—, —NH—, —NR⁶—,—S—, and —S(O)₂—. In some embodiments, R⁴ and R⁵ attached to the same Natom are taken together with the N atom to which they are attached toform a 4-, 5- or 6-membered heterocycle additionally containing 0 or 1oxygen heteroatom. In other embodiments, R⁴ and R⁵ attached to the sameN atom are taken together with the N atom to which they are attached toform an optionally substituted 4-, 5-, or 6-membered ring heterocycleadditionally containing 1 heteroatoms selected from —O—, —NH—, —NR⁶—,—S—, and —S(O)₂—. In other embodiments, R⁴ and R⁵ attached to the same Natom are taken together with the N atom to which they are attached toform a 4-, 5-, or 6-membered ring heterocycle additionally containing 1oxygen heteroatom. In other embodiments, R⁴ and R⁵ attached to the sameN atom are taken together with the N atom to which they are attached toform a 4-, 5-, or 6-membered ring.

In certain embodiments, R⁴ and R⁵ are each independently optionallysubstituted with halo, alkyl, hydroxy, alkoxy, or fluoroalkyl. In someembodiments, R⁴ and R⁵ are each independently optionally substitutedwith fluoro or C₁₋₆ alkyl. In some embodiments, R⁴ and R⁵ are eachindependently optionally substituted with fluoro or methyl.

In some embodiments, R⁶ is optionally substituted alkyl, fluoroalkyl,optionally substituted aryl, optionally substituted carbocyclyl, oroptionally substituted heterocyclyl. In some embodiments, R⁶ isoptionally substituted alkyl, fluoroalkyl, optionally substitutedcarbocyclyl, or optionally substituted heterocyclyl. In someembodiments, R⁶ is alkyl, aryl, carbocyclyl, or heterocyclyl. In someembodiments, R⁶ is alkyl, carbocyclyl, or heterocyclyl. In someembodiments, R⁶ is alkyl, carbocyclyl, or fluoroalkyl. In someembodiments, R⁶ is C₁₋₆ alkyl, C₁₋₆ fluoroalkyl, C₃₋₆ carbocyclyl, orC₃₋₆ heterocyclyl. In certain embodiments, R⁶ is C₁₋₆ alkyl. In certainembodiments, R⁶ is methyl, ethyl, propyl, iso-propyl, butyl, sec-butyl,iso-butyl, or tert-butyl. In some embodiments, R⁶ is optionallysubstituted phenyl.

In some embodiments, R⁷ is alkyl, carbocyclyl, optionally substitutedaryl, optionally substituted aralkyl, or optionally substitutedheterocyclyl. In some embodiments, R⁷ is C₁₋₆ alkyl, C₃₋₆ carbocyclyl,or aryl optionally substituted with halo or alkyl. In some embodiments,R⁷ is C₁₋₆ alkyl, C₃₋₆ carbocyclyl, or phenyl optionally substitutedwith halo or alkyl. In some embodiments, R⁷ is optionally substitutedbenzyl. In some embodiments, R⁷ is C₃₋₆ carbocyclyl. In someembodiments, R⁷ is phenyl. In some embodiments, R⁷ is phenyl substitutedwith 1-4 C₁₋₆ alkyl or fluoro substituents. In some embodiments, R⁷ isphenyl substituted with a C₁₋₆ alkyl or fluoro substituent. In someembodiments, R⁷ is alkyl, carbocyclyl, aralkyl, or heterocyclyl.

In certain embodiments, R⁷ is optionally substituted with halo, alkyl,hydroxy, alkoxy, or fluoroalkyl. In some embodiments, R⁷ is optionallysubstituted with fluoro or C₁₋₆ alkyl. In some embodiments, R⁷ isoptionally substituted with fluoro or methyl.

In some embodiments, each R¹³ is independently hydrogen, optionallysubstituted alkyl, haloalkyl, optionally substituted carbocyclyl,optionally substituted heteroalkyl, optionally substituted aryl,optionally substituted aralkyl, optionally substituted heterocyclyl, oroptionally substituted heteroaryl. In some embodiments, each R¹³ isindependently hydrogen, optionally substituted alkyl, optionallysubstituted carbocyclyl, optionally substituted heteroalkyl, oroptionally substituted aryl. In some embodiments, each R¹³ isindependently optionally substituted alkyl, optionally substitutedcarbocyclyl, optionally substituted heteroalkyl, optionally substitutedaryl, or heteroaryl. In some embodiments, each R¹³ is independentlyalkyl or aryl. In some embodiments, each R¹³ is independently hydrogenor C₁₋₆ alkyl. In some embodiments, each R¹³ is independently hydrogen,methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, sec-butyl,tert-butyl, pentyl or hexyl. In some embodiments, each R¹³ isindependently hydrogen, methyl, ethyl, propyl, iso-propyl, butyl, ortert-butyl. In some embodiments, each R¹³ is independently hydrogen ormethyl. In some embodiments, R¹³ is H. In other embodiments, R¹³ isalkyl. In other embodiments, R¹³ is aryl.

Any combination of the groups described above for the various variablesis contemplated herein. Throughout the specification, groups andsubstituents thereof are chosen by one skilled in the field to providestable moieties and compounds.

In some embodiments, the substituted steroidal derivative compounddescribed in Formulas provided herein has a structure provided in Table1.

TABLE 1 Mass, # Structure [M + H]⁺ 1

500.5 2

502.4 3

489.4 4

518.5 5

475.4 6

488.5 7

516.3 8

516.5 9

502.4 10

488.4 11

516.5 12

— 13

446.3 14

506.5 15

520.4 16

516.5 17

476.4 18

486.4 19

474.4 20

529.4 21

500.5 22

564.3 23

432.4 24

557.5 25

615.3 26

418.3 27

593.4 28

498.4 29

526.3 30

460.4 31

468.4 32

—

In some embodiments, the substituted steroidal derivative compounddescribed in Formulas provided herein has a structure provided in Table2.

TABLE 2 No. Structure  1a

 2a

 3a

 4a

 5a

 6a

 7a

 8a

 9a

10a

11a

12a

13a

14a

Preparation of the Substituted Steroidal Derivative Compounds

The compounds used in the reactions described herein are made accordingto organic synthesis techniques known to those skilled in this art,starting from commercially available chemicals and/or from compoundsdescribed in the chemical literature. “Commercially available chemicals”are obtained from standard commercial sources including Acros Organics(Pittsburgh, Pa.), Aldrich Chemical (Milwaukee, Wis., including SigmaChemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), AvocadoResearch (Lancashire, U.K.), BDH Inc. (Toronto, Canada), Bionet(Cornwall, U.K.), Chemservice Inc. (West Chester, Pa.), CrescentChemical Co. (Hauppauge, N.Y.), Eastman Organic Chemicals, Eastman KodakCompany (Rochester, N.Y.), Fisher Scientific Co. (Pittsburgh, Pa.),Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan,Utah), ICN Biomedicals, Inc. (Costa Mesa, Calif.), Key Organics(Cornwall, U.K.), Lancaster Synthesis (Windham, N.H.), MaybridgeChemical Co. Ltd. (Cornwall, U.K.), Parish Chemical Co. (Orem, Utah),Pfaltz & Bauer, Inc. (Waterbury, Conn.), Polyorganix (Houston, Tex.),Pierce Chemical Co. (Rockford, Ill.), Riedel de Haen AG (Hanover,Germany), Spectrum Quality Product, Inc. (New Brunswick, N.J.), TCIAmerica (Portland, Oreg.), Trans World Chemicals, Inc. (Rockville, Md.),and Wako Chemicals USA, Inc. (Richmond, Va.).

Suitable reference books and treatise that detail the synthesis ofreactant useful in the preparation of compounds described herein, orprovide references to articles that describe the preparation, includefor example, “Synthetic Organic Chemistry”, John Wiley & Sons, Inc., NewYork; S. R. Sandler et al., “Organic Functional Group Preparations,” 2ndEd., Academic Press, New York, 1983; H. O. House, “Modern SyntheticReactions”, 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif. 1972; T. L.Gilchrist, “Heterocyclic Chemistry”, 2nd Ed., John Wiley & Sons, NewYork, 1992; J. March, “Advanced Organic Chemistry: Reactions, Mechanismsand Structure”, 4th Ed., Wiley-Interscience, New York, 1992. Additionalsuitable reference books and treatise that detail the synthesis ofreactants useful in the preparation of compounds described herein, orprovide references to articles that describe the preparation, includefor example, Fuhrhop, J. and Penzlin G. “Organic Synthesis: Concepts,Methods, Starting Materials”, Second, Revised and Enlarged Edition(1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, R. V. “OrganicChemistry, An Intermediate Text” (1996) Oxford University Press, ISBN0-19-509618-5; Larock, R. C. “Comprehensive Organic Transformations: AGuide to Functional Group Preparations” 2nd Edition (1999) Wiley-VCH,ISBN: 0-471-19031-4; March, J. “Advanced Organic Chemistry: Reactions,Mechanisms, and Structure” 4th Edition (1992) John Wiley & Sons, ISBN:0-471-60180-2; Otera, J. (editor) “Modern Carbonyl Chemistry” (2000)Wiley-VCH, ISBN: 3-527-29871-1; Patai, S. “Patai's 1992 Guide to theChemistry of Functional Groups” (1992) Interscience ISBN: 0-471-93022-9;Solomons, T. W. G. “Organic Chemistry” 7th Edition (2000) John Wiley &Sons, ISBN: 0-471-19095-0; Stowell, J. C., “Intermediate OrganicChemistry” 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2;“Industrial Organic Chemicals: Starting Materials and Intermediates: AnUllmann's Encyclopedia” (1999) John Wiley & Sons, ISBN: 3-527-29645-X,in 8 volumes; “Organic Reactions” (1942-2000) John Wiley & Sons, in over55 volumes; and “Chemistry of Functional Groups” John Wiley & Sons, in73 volumes.

Specific and analogous reactants are optionally identified through theindices of known chemicals prepared by the Chemical Abstract Service ofthe American Chemical Society, which are available in most public anduniversity libraries, as well as through on-line databases (contact theAmerican Chemical Society, Washington, D.C. for more details). Chemicalsthat are known but not commercially available in catalogs are optionallyprepared by custom chemical synthesis houses, where many of the standardchemical supply houses (e.g., those listed above) provide customsynthesis services. A reference for the preparation and selection ofpharmaceutical salts of the substituted steroidal derivative compoundsdescribed herein is P. H. Stahl & C. G. Wermuth “Handbook ofPharmaceutical Salts”, Verlag Helvetica Chimica Acta, Zurich, 2002.

Pharmaceutical Compositions of the Substituted Steroidal DerivativeCompounds

In certain embodiments, the substituted steroidal derivative compound asdescribed herein is administered as a pure chemical. In otherembodiments, the substituted steroidal derivative compound describedherein is combined with a pharmaceutically suitable or acceptablecarrier (also referred to herein as a pharmaceutically suitable (oracceptable) excipient, physiologically suitable (or acceptable)excipient, or physiologically suitable (or acceptable) carrier) selectedon the basis of a chosen route of administration and standardpharmaceutical practice as described, for example, in Remington: TheScience and Practice of Pharmacy (Gennaro, 21^(st) Ed. Mack Pub. Co.,Easton, Pa. (2005)).

Provided herein is a pharmaceutical composition comprising at least onesubstituted steroidal derivative compound, or a stereoisomer,pharmaceutically acceptable salt, hydrate, solvate, or N-oxide thereof,together with one or more pharmaceutically acceptable carriers. Thecarrier(s) (or excipient(s)) is acceptable or suitable if the carrier iscompatible with the other ingredients of the composition and notdeleterious to the recipient (i.e., the subject) of the composition.

One embodiment provides a pharmaceutical composition comprising acompound of any of the Formulas provided herein, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable excipient.

In certain embodiments, the substituted steroidal derivative compound asdescribed by any of the Formulas provided herein is substantially pure,in that it contains less than about 5%, or less than about 1%, or lessthan about 0.1%, of other organic small molecules, such as unreactedintermediates or synthesis by-products that are created, for example, inone or more of the steps of a synthesis method.

Suitable oral dosage forms include, for example, tablets, pills,sachets, or capsules of hard or soft gelatin, methylcellulose or ofanother suitable material easily dissolved in the digestive tract. Insome embodiments, suitable nontoxic solid carriers are used whichinclude, for example, pharmaceutical grades of mannitol, lactose,starch, magnesium stearate, sodium saccharin, talcum, cellulose,glucose, sucrose, magnesium carbonate, and the like. (See, e.g.,Remington: The Science and Practice of Pharmacy (Gennaro, 21^(st) Ed.Mack Pub. Co., Easton, Pa. (2005)).

The dose of the composition comprising at least one substitutedsteroidal derivative compound as described herein differ, depending uponthe patient's (e.g., human) condition, that is, stage of the disease,general health status, age, and other factors.

Pharmaceutical compositions are administered in a manner appropriate tothe disease to be treated (or prevented). An appropriate dose and asuitable duration and frequency of administration will be determined bysuch factors as the condition of the patient, the type and severity ofthe patient's disease, the particular form of the active ingredient, andthe method of administration. In general, an appropriate dose andtreatment regimen provides the composition(s) in an amount sufficient toprovide therapeutic and/or prophylactic benefit (e.g., an improvedclinical outcome, such as more frequent complete or partial remissions,or longer disease-free and/or overall survival, or a lessening ofsymptom severity. Optimal doses are generally determined usingexperimental models and/or clinical trials. The optimal dose dependsupon the body mass, weight, or blood volume of the patient.

Oral doses typically range from about 1.0 mg to about 1000 mg, one tofour times, or more, per day.

Use of the Substituted Steroidal Derivative Compounds GlucocorticoidReceptor Modulators

Mifepristone is a non-selective modulator of several nuclear receptors.Mifepristone has been referred to as a GR antagonist, a progesteronereceptor (PR) antagonist, a GR partial agonist, an androgen receptor(AR) antagonist and an AR partial agonist in the scientific literature.The activity observed at multiple hormone receptors leads to variousundesirable side effects and in some instances, the promotion of cancer.Thus, AR agonism is an undesirable feature for GR antagonists used inthe treatment of cancer (e.g., AR positive or AR dependent cancersincluding “castration resistant” prostate cancer (CRPC), breast cancer,or ovarian cancer). Antagonists of GR that have minimized binding toother hormone receptors, such as the androgen receptor (AR), are neededto effectively treat the diseases described herein with reduced sideeffects.

Some embodiments provided herein describe compounds that are modulatorsof glucocorticoid receptors (GR). In some embodiments, the compoundsalter the level and/or activity of GR. In some embodiments, thecompounds described herein are GR inhibitors. In some embodiments, theGR inhibitors are GR antagonists. In some instances, glucocorticoidreceptor antagonists bind to the receptor and prevent glucocorticoidreceptor agonists from binding and eliciting GR mediated events,including transcription. Thus, in some embodiments, the compoundsdescribed herein inhibit GR transcriptional activation activity. In someembodiments, the compounds described herein are selective GRantagonists. In some embodiments, the compounds described herein are notGR agonists. In some embodiments, the compounds described herein are notGR partial agonists. In some embodiments, the GR inhibitors lessencortisol activity in cells and make secondary therapeutic agents moreeffective.

GR antagonists are useful for treating or preventing weight gain (e.g.,Olanzapine induced weight gain), uterine fibrosis, alcoholism, alcoholabuse disorders, cocaine dependence, bipolar depression, adrenalhypercortisolism, post-traumatic stress disorder, anxiety disorders,mood disorders, hyperglycemia, and to induce abortion.

In some embodiments, the GR inhibitors described herein are alsoandrogen receptor (AR) signaling inhibitors. In certain embodiments, theAR signaling inhibitors are AR antagonists. In some instances, ARantagonists bind to AR and prevent AR agonists from binding andeliciting AR mediated events, including transcription. In otherembodiments, the GR inhibitors are not androgen receptor (AR) signalinginhibitors. In these instances, the GR inhibitors do not significantlyactivate AR levels and/or activity. In some embodiments, the GRinhibitors are not AR agonists.

In some embodiments, the GR inhibitors described herein have minimizedbinding to the androgen receptor (AR). In some embodiments, thecompounds described herein are not AR agonists. In some embodiments, thecompounds described herein are not partial AR agonists. In someembodiments, the compounds described herein have minimized partial ARagonism compared to mifepristone.

In some embodiments, the GR inhibitors described herein are not partialAR agonists or partial GR agonists.

In some embodiments, the GR inhibitors described herein do not modulateprogesterone receptors. In some embodiments, the GR inhibitors describedherein are not progesterone receptor (PR) inhibitors. In theseinstances, the GR inhibitors do not significantly activate PR levelsand/or activity. In some embodiments, the GR inhibitors are not PRagonists. In some embodiments, the GR inhibitors are not PR partialagonists. In some embodiments, the GR inhibitors are not PR antagonists.

In some embodiments, the GR inhibitors (e.g., GR antagonists) areselective inhibitors. In some embodiments, use of the GR inhibitors in apatient does not cause or result in vaginal bleeding, cramping, nausea,vomiting, diarrhea, dizziness, back pain, weakness, tiredness, orcombinations thereof. In certain embodiments, use of the GR inhibitorsin a patient does not cause or result in vaginal bleeding. In certainembodiments, use of the GR inhibitors in a patient does not cause orresult in cramping. In some embodiments, use of the GR inhibitors in apatient does not cause or result in allergic reactions, low bloodpressure, loss of consciousness, shortness of breath, rapid heartbeat,or combinations thereof.

Methods of Treatment Cancer

One embodiment provides a method of treating cancer in a subject in needthereof, comprising administering to the subject a compound of any ofthe Formulas provided herein, or a pharmaceutically acceptable saltthereof. In some embodiments, a GR inhibitor described herein is used incombination with a second therapeutic agent (e.g., an anti-cancer agent)for treating cancer. In some embodiments, the combination of the GRinhibitor with the second therapeutic agent (e.g., an anti-cancer agent)provides a more effective initial therapy for treating cancer comparedto the second therapeutic agent (e.g., an anti-cancer agent)administered alone. In some embodiments, a GR inhibitor described hereinis used in combination with one or more additional therapeutic agents(e.g., anti-cancer agents) for treating cancer. In some embodiments, thecombination of the GR inhibitor with the one or more additionaltherapeutic agents (e.g., an anti-cancer agents) provides a moreeffective initial therapy for treating cancer compared to the one ormore therapeutic agents (e.g., an anti-cancer agents) administeredalone.

In some embodiments, the cancer is chemoresistant cancer, radioresistant cancer, or refractory cancer. In some embodiments, the canceris relapsed cancer, persistent cancer, or recurrent cancer. Anotherembodiment provided herein describes a method of reducing incidences ofcancer recurrence. Also provided here in some embodiments, is a methodfor treating a chemo-resistant cancer.

Prostate Cancer

Prostate cancer is the second most common cause of cancer death in menin the United States, and approximately one in every six American menwill be diagnosed with the disease during his lifetime. Treatment aimedat eradicating the tumor is unsuccessful in 30% of men.

One embodiment provides a method of treating prostate cancer in asubject in need thereof, comprising administering to the subject acompound of any of the Formulas provided herein, or a pharmaceuticallyacceptable salt thereof. In some embodiments, a GR inhibitor describedherein is used in combination with a second therapeutic agent (e.g., ananti-cancer agent) for treating prostate cancer. In some embodiments,the combination of the GR inhibitor with the second therapeutic agent(e.g., an anti-cancer agent) provides amore effective initial therapyfor treating prostate cancer compared to the second therapeutic agent(e.g., an anti-cancer agent) administered alone. In some embodiments, aGR inhibitor described herein is used in combination with one or moreadditional therapeutic agents (e.g., anti-cancer agents) for treatingprostate cancer. In some embodiments, the combination of the GRinhibitor with the one or more additional therapeutic agents (e.g., ananti-cancer agents) provides a more effective initial therapy fortreating prostate cancer compared to the one or more therapeutic agents(e.g., an anti-cancer agents) administered alone.

In some embodiments, the prostate cancer is chemoresistant cancer, radioresistant cancer, antiandrogen resistant, or refractory cancer. In someembodiments, the prostate cancer is relapsed cancer, persistent cancer,or recurrent cancer.

In some embodiments, the prostate cancer is acinar adenocarcinoma,atrophic carcinoma, foamy carcinoma, colloid carcinoma, or signet ringcarcinoma. In some embodiments, the prostate cancer is ductaladenomcarcinoma, transitional cell cancer, urothelial cancer, squamouscell cancer, carcinoid cancer, small cell cancer, sarcoma cancer, orsarcomatoid cancer. In some embodiments, the prostate cancer ismetastatic castration-resistant prostate cancer, doubly-resistantprostate cancer, castration-resistant prostate cancer, hormone-resistantprostate cancer, androgen-independent, or androgen-refractory cancer.

In some instances, antiandrogens are useful for the treatment ofprostate cancer during its early stages. In some instances, prostatecancer cells depend on androgen receptor (AR) for their proliferationand survival. Some prostate cancer patients are physically castrated orchemically castrated by treatment with agents that block production oftestosterone (e.g. GnRH agonists), alone or in combination withantiandrogens, which antagonize effects of any residual testosterone.

In some instances, prostate cancer advances to a hormone-refractorystate in which the disease progresses despite continued androgenablation or antiandrogen therapy. The hormone-refractory state to whichmost patients eventually progresses in the presence of continuedandrogen ablation or anti-androgen therapy is known as “castrationresistant” prostate cancer (CRPC). CRPC is associated with anoverexpression of AR. AR is expressed in most prostate cancer cells andoverexpression of AR is necessary and sufficient forandrogen-independent growth of prostate cancer cells. Failure inhormonal therapy, resulting from development of androgen-independentgrowth, is an obstacle for successful management of advanced prostatecancer.

While a small minority of CRPC does bypass the requirement for ARsignaling, the vast majority of CRPC, though frequently termed “androgenindependent prostate cancer” or “hormone refractory prostate cancer,”retains its lineage dependence on AR signaling.

Recently approved therapies that target androgen receptor (AR) signalingsuch as abiraterone and enzalutamide have been utilized for treatingCRPC. Despite these successes, sustained response with these agents islimited by acquired resistance which typically develops within 6-12months. Doubly resistant prostate cancer is characterized in that tumorcells have become castration resistant and overexpress AR, a hallmark ofCRPC. However, cells remain resistant when treated with secondgeneration antiandrogens. Doubly resistant prostate cancer cells arecharacterized by a lack of effectiveness of second generationantiandrogens in inhibiting tumor growth.

As discussed above, resistant prostate cancer (e.g., doubly resistantand castration resistant prostate cancers) occurs when cancer cellsoverexpress androgen receptors (AR). AR target gene expression isinhibited when the cells are treated with a second generationantiandrogen. In some instances, increased signaling through theglucocorticoid receptor (GR) compensates for inhibition of androgenreceptor signaling in resistant prostate cancer. Double resistantprostate cancer develops when expression of a subset of those AR targetgenes is restored. In some instances, GR activation is responsible forthis target gene activation. In some embodiments, GR transcription isactivated in patients susceptible to or suffering from resistantprostate cancer (e.g., doubly resistant and castration resistantprostate cancers). In some instances, GR upregulation in cancer cellsconfers resistance to antiandrogens.

Some embodiments provided herein describe the use of the GR inhibitorsfor treating prostate cancer in a subject in need thereof, includingdoubly resistant prostate cancer and castration resistant prostatecancer. In some embodiments, the subject in need has elevated tumor GRexpression. In some embodiments, the GR inhibitor is also an ARsignaling inhibitor or antiandrogen.

In some embodiments, the GR inhibitor is used in combination with asecond therapeutic agent. In some embodiments, the GR inhibitor is usedin combination with one or more additional therapeutic agents. In someembodiments, the second or additional agent is an anti-cancer agent. Incertain embodiments, the anti-cancer agent is useful for AR positive orAR negative prostate cancer.

In some embodiments, the second or additional agent is an AR signalinginhibitor or antiandrogen. In certain embodiments, the AR signalinginhibitor is an AR antagonist. In some embodiments, the second oradditional therapeutic agent is selected from finasteride, dutasteride,alfatradiol, cyproterone acetate, spironolactone, danazol, gestrinone,ketoconazole, abiraterone acetate, enzalutamide, ARN-509, danazol,gestrinone, danazol, simvastatin, aminoglutethimide, atorvastatin,simvastatin, progesterone, cyproterone acetate, medroxyprogesteroneacetate, megestrol acetate, chlormadinone acetate, spironolactone,drospirenone, estradiol, ethinyl estradiol, diethylstilbestrol,conjugated equine estrogens, buserelin, deslorelin, gonadorelin,goserelin, histrelin, leuprorelin, nafarelin, triptorelin, abarelix,cetrorelix, degarelix, ganirelix, or any combinations or any saltsthereof. In some embodiments, the second or additional therapeutic agentis selected from flutamide, nilutamide, bicalutamide, enzalutamide,apalutamide, cyproterone acetate, megestrol acetate, chlormadinoneacetate, spironolactone, canrenone, drospirenone, ketoconazole,topilutamide, cimetidine, or any combinations or any salts thereof. Insome embodiments, the AR signaling inhibitor is 3,3′-diindolylmethane(DIM), abiraterone acetate, ARN-509, bexlosteride, bicalutamide,dutasteride, epristeride, enzalutamide, finasteride, flutamide,izonsteride, ketoconazole, N-butylbenzene-sulfonamide, nilutamide,megestrol, steroidal antiandrogens, turosteride, or any combinationsthereof. In some embodiments, the AR signaling inhibitor is flutamide,nilutamide, bicalutamide, or megestrol. In some embodiments, the ARsignaling inhibitor is ARN-509. In other embodiments, the AR signalinginhibitor is enzalutamide.

In some embodiments, the anti-cancer agent is mitoxantrone,estramustine, etoposide, vinblastine, carboplatin, vinorelbine,paclitaxel, daunomycin, darubicin, epirubicin, docetaxel, cabazitaxel,or doxorubicin. In some embodiments, the anti-cancer agent ispaclitaxel, daunomycin, darubicin, epirubicin, docetaxel, cabazitaxel,or doxorubicin. In certain embodiments, the anti-cancer agent isdocetaxel.

Breast Cancer

Breast cancer is the second leading cause of cancer among women in theUnited States. Triple-negative breast cancers are among the mostaggressive and difficult to treat of all the breast cancer types.Triple-negative breast cancer is a form of the disease in which thethree receptors that fuel most breast cancer growth—estrogen,progesterone and the HER-2—are not present. Because the tumor cells lackthese receptors, treatments that target estrogen, progesterone and HER-2are ineffective. Approximately 40,000 women are diagnosed withtriple-negative breast cancer each year. It is estimated that more thanhalf of these women's tumor cells express significant amounts of GR.

In some instances, GR expression is associated with a poor prognosis inestrogen receptor (ER)-negative early stage breast cancer. In someinstances, GR activation in triple-negative breast cancer cellsinitiates an anti-apoptotic gene expression profile that is associatedwith inhibiting chemotherapy-induced tumor cell death. GR activity inthese cancer cells correlate with chemotherapy resistance and increasedrecurrence of cancer.

Provided herein in some embodiments are methods of treating breastcancer, the method comprising administering to a subject in need thereofa compound of any of the Formulas provided herein, or a pharmaceuticallyacceptable salt thereof. In some embodiments, a GR inhibitor describedherein is used in combination with a second therapeutic agent (e.g., achemotherapeutic agent) for treating breast cancer. In some embodiments,the combination of the GR inhibitor with the second therapeutic agent(e.g., a chemotherapeutic agent) provides a more effective initialtherapy for treating breast cancer compared to the second therapeuticagent (e.g., a chemotherapeutic agent) administered alone. In someembodiments, a GR inhibitor described herein is used in combination withone or more additional therapeutic agents (e.g., anti-cancer agents) fortreating breast cancer. In some embodiments, the combination of the GRinhibitor with the one or more additional therapeutic agents (e.g., ananti-cancer agents) provides amore effective initial therapy fortreating breast cancer compared to the one or more therapeutic agents(e.g., an anti-cancer agents) administered alone.

In some embodiments, the breast cancer is chemoresistant cancer, radioresistant cancer, or refractory cancer. In some embodiments, the breastcancer is relapsed cancer, persistent cancer, or recurrent cancer.Breast cancers may include, but are not limited to, ductal carcinoma,invasive ductal carcinoma, tubular carcinoma of the breast, medullarycarcinoma of the breast, mecinous carcinoma of the breast, papillarycarcinoma of the breast, cribriform carcinoma of the breast, invasivelobular carcinoma, inflammatory breast cancer, lobular carcinoma insitu, male breast cancer, Paget disease of the nipple, phyllodes tumorof the breast, recurrent and metastatic breast cancer, triple-negativebreast cancer, or combinations thereof.

In some embodiments, the breast cancer is recurrent and metastaticbreast cancer, triple-negative breast cancer, or combinations thereof.In some embodiments, the breast cancer is chemoresistant triple-negativebreast cancer or estrogen receptor (ER) negative breast cancer. In someembodiments, the breast cancer is chemoresistant triple-negative breastcancer. In some embodiments, the breast cancer is estrogen receptor (ER)negative breast cancer. In some embodiments, the breast cancer is GR+triple-negative breast cancer. In some embodiments, the breast cancer isGR+ estrogen receptor (ER) negative breast cancer.

Some embodiments provided herein describe the use of GR inhibitors fortreating breast cancer in a patient, including triple negative breastcancer or ER negative breast cancer. In some embodiments, GR inhibitorsinhibit the anti-apoptotic signaling pathways of GR and increase thecytotoxic efficiency of secondary chemotherapeutic agents. In someembodiments, the GR inhibitors described herein enhance the efficacy ofchemotherapy in breast cancer patients, such as triple negative breastcancer patients. In some embodiments, the breast cancer patient haselevated tumor GR expression.

In some embodiments, a GR inhibitor described herein is used incombination with a second therapeutic agent, such as chemotherapy orimmunotherapy. In some embodiments, a GR inhibitor described herein isused in combination with one or more additional therapeutic agents. Insome embodiments, the second or additional chemotherapeutic agent iscisplatin, carboplatin, cyclophosphamide, capecitabine, gemcitabine,paclitaxel, nab-paclitaxel, altretamine, docetaxel, epirubicin,melphalan, methotrexate, mitoxantrone, ixabepilone, ifosfamide,irinotecan, eribulin, etoposide, doxorubicin, liposomal doxorubicin,camptothecin, pemetrexed, topotecan, vinorelbine, daunorubicin,fluorouracil, mitomycin, thiotepa, vincristine, everolimus, veliparib,glembatumumab vedotin, pertuzumab, trastuzumab, or any combinations orany salts thereof. In some embodiments, the second or additionaltherapeutic agent is an anti-PD-L1 agent. In certain embodiments, theanti-PD-L1 agent is MPDL3280A or avelumab. In some embodiments, thesecond or additional therapeutic agent is an anti-PD1 agent. In certainembodiments the anti-PD1 agent is nivolumab or permbrolizumab.

Some embodiments provided herein describe methods of treating estrogenpositive breast cancer. In some instances, estrogen positive breastcancer patients become resistant to estrogen receptor modulators. Insome embodiments, the GR inhibitors described herein enhance theefficacy of estrogen receptor modulators in estrogen positive breastcancer patients. In some embodiments, the breast cancer patient haselevated tumor GR expression. In some embodiments, a GR inhibitordescribed herein is used in combination with an estrogen receptormodulator. In some embodiments, the estrogen receptor modulator istamoxifen, raloxifene, toremifene, tibolone, fulvestrant, lasofoxifene,clomifene, ormeloxifene, or ospemifene. In some embodiments, theestrogen receptor modulator is tamoxifen, raloxifene, toremifene,tibolone, or fulvestrant. In some embodiments, the estrogen receptormodulator is tamoxifen, raloxifene, or toremifene. In certainembodiments, the estrogen receptor modulator is tamoxifen.

Ovarian Cancer

Ovarian cancer is the leading cause of death from gynecologicmalignancies. Some ovarian cancers (e.g., high grade serous ovariancancer) are initially sensitive to platinum-based therapy, but relapserates remain high.

One embodiment provides a method of treating ovarian cancer in a patientin need thereof, comprising administering to the patient a compound ofany of the Formulas provided herein, or a pharmaceutically acceptablesalt thereof. In some embodiments, the patient has elevated tumor GRexpression. In some embodiments, a GR inhibitor described herein is usedin combination with a second therapeutic agent (e.g., a chemotherapeuticagent) for treating ovarian cancer. In some embodiments, the combinationof the GR inhibitor with the second therapeutic agent (e.g., achemotherapeutic agent) provides a more effective initial therapy fortreating ovarian cancer compared to the second therapeutic agent (e.g.,a chemotherapeutic agent) administered alone. In some embodiments, a GRinhibitor described herein is used in combination with one or moreadditional therapeutic agents (e.g., anti-cancer agents) for treatingovarian cancer. In some embodiments, the combination of the GR inhibitorwith the one or more additional therapeutic agents (e.g., an anti-canceragents) provides a more effective initial therapy for treating ovariancancer compared to the one or more therapeutic agents (e.g., ananti-cancer agents) administered alone.

In some instances, GR activation increases resistance to chemotherapy inovarian cancer (e.g., high-grade serous ovarian cancer). In someinstances, GR activation significantly inhibits chemotherapy inducedapoptosis in ovarian cancer cells. Provided herein in some embodimentsare methods of treating ovarian cancer in a subject, the methodcomprising treating the subject with a GR inhibitor (e.g., GRantagonist) to improve sensitivity to chemotherapy. In some embodiments,the ovarian cancer has become resistant to chemotherapy. In someembodiments, the ovarian cancer cells are resistant to cisplatin,paclitaxel, carboplatin, gemcitabine, alone or in combination. In someembodiments, the GR inhibitor or antagonist reverses the cell survivaleffect.

Ovarian cancers may include, but are not limited to, epithelial ovariancancers, such as serous epithelial ovarian cancer, endometrioidepithelial ovarian cancer, clear cell epithelial ovarian cancer,mucinous epithelial ovarian cancer, undifferentiated or unclassifiableepithelial ovarian cancer, refractory ovarian cancer, sex cord-stromaltumors, Sertoli and Sertoli-Leydig cell tumors, germ cell tumors, suchas dysgerminoma and nondysgerminomatous tumors, Brenner tumors, primaryperitoneal carcinoma, fallopian tube cancer, or combinations thereof.

In some embodiments, the GR inhibitor is used in combination with atleas a second therapeutic agent, such as chemotherapy or immunotherapy.In some embodiments, the GR inhibitor is used in combination with one ormore additional therapeutic agents. In some embodiments, the second oradditional chemotherapeutic agent is cisplatin, carboplatin,cyclophosphamide, capecitabine, gemcitabine, paclitaxel, nab-paclitaxel,altretamine, docetaxel, epirubicin, melphalan, methotrexate,mitoxantrone, ixabepilone, ifosfamide, irinotecan, eribulin, etoposide,doxorubicin, liposomal doxorubicin, camptothecin, pemetrexed, topotecan,vinorelbine, daunorubicin, fluorouracil, mitomycin, thiotepa,vincristine, everolimus, veliparib, glembatumumab vedotin, pertuzumab,trastuzumab, or any combinations or any salts thereof. In someembodiments, the second or additional chemotherapeutic agent isgemcitabine. In some embodiments, the second or additionalchemotherapeutic agent is carboplatin. In some embodiments, the secondor additional chemotherapeutic agent is cisplatin. In some embodiments,the second or additional agent is paclitaxel. In some embodiments, theGR inhibitor is used in combination with gemcitabine and carboplatin. Insome embodiments, the GR inhibitor is used in combination withcarboplatin and cisplatin. In some embodiments, the second or additionaltherapeutic agent is an anti-PD-L1 agent. In certain embodiments, theanti-PD-L1 agent is MPDL3280A or avelumab. In some embodiments, thesecond or additional therapeutic agent is an anti-PD1 agent. In certainembodiments, the anti-PD1 agent is nivolumab or permbrolizumab.

Non-Small Cell Lung Cancer

One embodiment provides a method of treating non-small cell lung cancer(NSCLC) in a patient in need thereof, comprising administering to thepatient a compound of any of the Formulas provided herein, or apharmaceutically acceptable salt thereof. In some embodiments, thepatient has elevated tumor GR expression. In some embodiments, a GRinhibitor described herein is used in combination with a secondtherapeutic agent (e.g., a chemotherapeutic agent) for treating NSCLC.In some embodiments, the combination of the GR inhibitor with the secondtherapeutic agent (e.g., a chemotherapeutic agent) provides amoreeffective initial therapy for treating NSCLC compared to the secondtherapeutic agent (e.g., a chemotherapeutic agent) administered alone.In some embodiments, a GR inhibitor described herein is used incombination with one or more additional therapeutic agents (e.g.,anti-cancer agents) for treating NSCLC. In some embodiments, thecombination of the GR inhibitor with the one or more additionaltherapeutic agents (e.g., an anti-cancer agents) provides a moreeffective initial therapy for treating NSCLC compared to the one or moretherapeutic agents (e.g., an anti-cancer agents) administered alone.

In some embodiments, the GR inhibitor is used in combination with atleast a second therapeutic agent, such as a chemotherapeutic agent orimmunotherapy. In some embodiments, the GR inhibitor is used incombination with one or more additional therapeutic agents. In someembodiments, the second or additional chemotherapeutic agent iscisplatin, carboplatin, cyclophosphamide, capecitabine, gemcitabine,paclitaxel, nab-paclitaxel, altretamine, docetaxel, epirubicin,melphalan, methotrexate, mitoxantrone, ixabepilone, ifosfamide,irinotecan, eribulin, etoposide, doxorubicin, liposomal doxorubicin,camptothecin, pemetrexed, topotecan, vinorelbine, vinblastine,daunorubicin, fluorouracil, mitomycin, thiotepa, vincristine,everolimus, veliparib, glembatumumab vedotin, pertuzumab, trastuzumab,or any combinations or any salts thereof. In some embodiments, thesecond or additional chemotherapeutic agent is gemcitabine. In someembodiments, the second or additional chemotherapeutic agent iscarboplatin. In some embodiments, the second or additionalchemotherapeutic agent is cisplatin. In some embodiments, the second oradditional agent is paclitaxel. In some embodiments, the GR inhibitor isused in combination with gemcitabine and carboplatin. In someembodiments, the GR inhibitor is used in combination with carboplatinand cisplatin. In some embodiments, the second or additional therapeuticagent is an anti-PD-L1 agent. In certain embodiments, the anti-PD-L1agent is MPDL3280A or avelumab. In some embodiments, the second oradditional therapeutic agent is an anti-PD1 agent. In certainembodiments, the anti-PD1 agent is nivolumab or permbrolizumab.

Hypocortisolism/Cushing's Disease

One embodiment provides a method of treating hypercortisolism orCushing's disease in a patient in need thereof, comprising administeringto the patient a compound of any of the Formulas provided herein, or apharmaceutically acceptable salt thereof.

Types of Cushing's disease include, but are not limited to, recurrentCushing's disease, refractory Cushing's disease, persistent Cushing'sdisease, endogenous Cushing's disease, spontaneous hypercortisolism,Adrenocorticotropic hormone dependent, Adrenocorticotropic hormoneindependent, or combinations thereof.

Causes of hypercortisolism may include, but are not limited to,prolonged exposure to cortisol, a tumor that produces excessivecortisol, a tumor that results in the excess production of cortisol, orcombinations thereof.

Other embodiments and uses will be apparent to one skilled in the art inlight of the present disclosures. The following examples are providedmerely as illustrative of various embodiments and shall not be construedto limit the invention in any way.

EXAMPLES I. Chemical Synthesis

Unless otherwise noted, reagents and solvents were used as received fromcommercial suppliers. Anhydrous solvents and oven-dried glassware wereused for synthetic transformations sensitive to moisture and/or oxygen.Yields were not optimized. Reaction times are approximate and were notoptimized. Column chromatography and thin layer chromatography (TLC)were performed on silica gel unless otherwise noted.

Example 1. Compound 17.(8S,9R,10R,11S,13S,14S,17S)-11-(4-(Dimethylamino)phenyl)-17-hydroxy-17-(3-methoxyprop-1-yn-1-yl)-10,13-dimethyl-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one

Step A.(8′S,9′S,10′R,13′S,14′S)-10′,13′-Dimethyl-1′,2′,4′,7′,8′,9′,10′,12′,13′,14′,15′,16′-dodecahydro-11′H-dispiro[[1,3]dioxolane-2,3′-cyclopenta[a]phenanthrene-17′,2″-[1,3]dioxolan]-11′-one

Adrenosterone (50.2 g, 1 eq) was dissolved in 390 ml DCM with 91 g oftrimethylorthoformate (5.2 eq) and 119 g of ethylene glycol (11.5 eq).Toluenesulfonic acid (1.9 g, 0.06 eq) was added. The reaction was heatedto 40° C. for 18 h. The dark colored solution was quenched with 4 mlpyridine. The reaction was concentrated to remove solvents. The residuewas taken up in DCM and washed with water. The organic layer was driedwith MgSO₄, filtered and concentrated to give 74.3 g of a mushy solid.The solid was purified to give 42.2 g (65%) of the title compound. m/z(ESI, +ve ion) 389.3 (M+H)⁺.

Step B.(8′S,9′S,10′R,13′R,14′S)-10′,13′-dimethyl-1′,4′,7′,8′,9′,10′,13′,14′,15′,16′-decahydro-2′H-dispiro[[1,3]dioxolane-2,3′-cyclopenta[a]phenanthrene-17′,2″-[1,3]dioxolan]-11′-yl1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate

Lithium diisopropylamide solution was prepared as follows. In anoven-dried 500 mL flask a solution of 125 mL THF and anhydrousdiisopropylamine (5.77 ml, 4.1 eq) was cooled in a dry ice-acetone bath.N-butyl lithium (25.1 ml, 4 eq, 1.6 M in hexanes) was added slowly andthe reaction was stirred for 25 min.

A separate flask was charged with the starting bis-ketal (Step A) (3.9g, 1 eq), azeotroped with toluene, dried under vacuum, flushed with Arand kept under an Ar balloon. 40 mL of THF was added to dissolve thebis-ketal. This solution was added slowly to the freshly prepared LDAsolution maintained at −78° C. The reaction was stirred for 30 min, thenperfluorobutanesulfonyl fluoride (5.4 ml, 3 eq) was added. The reactionwas maintained in the cold bath for another hour. The bath was removedand the mixture allowed to stir at rt overnight. After 24 h, additional2.5 mL perfluorobutanesulfonyl fluoride was added and the reaction wasstirred overnight again. Saturated aq. NH₄Cl was added to the reaction,followed by extraction with EtOAc. The organic layer was washed withbrine and dried with MgSO₄. After concentration under vacuum, theresidue was purified by silica gel chromatography to give the desiredproduct as a light yellow solid (3.7 g, 55%). m/z (ESI, +ve ion) 671.2(M+H)⁺.

Step C. tert-Butyl(4-((8′S,9′S,10′R,13′R,14′S)-10′,13′-dimethyl-1′,4′,7′,8′,9′,10′,13′,14′,15′,16′-decahydro-2′H-dispiro[[1,3]dioxolane-2,3′-cyclopenta[a]phenanthrene-17′,2″-[1,3]dioxolan]-11′-yl)phenyl)(methyl)carbamate

A flask was charged with(8′S,9′S,10′R,13′R,14′S)-10′,13′-dimethyl-1′,4′,7′,8′,9′,10′,13′,14′,15′,16′-decahydro-2′H-dispiro[[1,3]dioxolane-2,3′-cyclopenta[a]phenanthrene-17′,2″-[1,3]dioxolan]-11′-yl1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate (Step B) (1.4 g, 1 eq),(4-((tert-butoxycarbonyl)(methyl)amino)phenyl)boronic acid (5.2 g, 10eq), lithium chloride (177 mg, 2 eq), and Pd(PPh₃)₄ (193 mg, 0.08 eq).Then toluene (36 mL), ethanol (18 mL), and Na₂CO₃ (2M, 7.8 mL, 7.5 eq)were added successively and the reaction mixture was degassed withargon. After the reaction was refluxed for 42 h, it was cooled to rt,quenched with aq. NaHCO₃ solution, and extracted with EtOAc. The organiclayer was separated, washed with saturated brine solution, dried withMgSO₄, filtered and concentrated to dryness in vacuo. Purification byflash silica gel column chromatography provided the title compound (1.1g, 92%) as a white solid.

Step D. tert-Butyl(4-((4a′R,5a′S,6a′S,6b′S,9a′R,11a′R,11b′R)-9a′,11b′-dimethyl-1′,5a′,6′,6a′,6b′,7′,8′,9a′,11a′,11b′-decahydro-2′H,4′H-dispiro[[1,3]dioxolane-2,3′-cyclopenta[1,2]phenanthro[8a,9-b]oxirene-9′,2″-[1,3]dioxolan]-11′-yl)phenyl)(methyl)carbamate

To a solution of tert-butyl(4-((8′S,9′S,10′R,13′R,14′S)-10′,13′-dimethyl-1′,4′,7′,8′,9′,10′,13′,14′,15′,16′-decahydro-2′H-dispiro[[1,3]dioxolane-2,3′-cyclopenta[a]phenanthrene-17′,2″-[1,3]dioxolan]-11′-yl)phenyl)(methyl)carbamate(Step C) (520 mg, 0.9 mmol) in DCM (10 mL) at 0° C. was added1,1,1,3,3,3-hexafluoropropan-2-one (0.14 mL, 0.99 mmol), followed by 30%hydrogen peroxide aqueous solution (0.37 mL, 4.5 mmol) and disodiumphosphate (383.3 mg, 2.7 mmol). The reaction mixture was stirred at 0°C. for 10 min and rt overnight. Additional aliquots of reagents (380 mgof disodium phosphate, 0.13 mL of CF₃COCF₃, 0.35 mL of 30% H₂O₂) wereadded at 24 h and 48 h time points. The reaction was quenched with 10%Na₂S₂O₃ solution and extracted with EtOAc. After washing with brine, theorganic layer was separated, dried with MgSO₄ and concentrated. Theresidue was purified by silica gel chromatography to provide 470 mg(88%) of desired epoxide as a white foamy solid.

Step E. tert-Butyl(4-((5′R,8′S,9′R,10′R,13′R,14′S)-5′-hydroxy-10′,13′-dimethyl-1′,4′,5′,6′,7′,8′,9′,10′,13′,14′,15′,16′-dodecahydro-2′H-dispiro[[1,3]dioxolane-2,3′-cyclopenta[a]phenanthrene-17′,2″-[1,3]dioxolan]-11′-yl)phenyl)(methyl)carbamate

A flask was charged with(tert-butyl(4-((4a′R,5a′S,6a′S,6b′S,9a′R,11a′R,11b′R)-9a′,11b′-dimethyl-1′,5a′,6′,6a′,6b′,7′,8′,9a′,11a′,11b′-decahydro-2′H,4′H-dispiro[[1,3]dioxolane-2,3′-cyclopenta[1,2]phenanthro[8a,9-b]oxirene-9′,2″-[1,3]dioxolan]-11′-yl)phenyl)(methyl)carbamate(Step D) (2.98 g, 6.02 mmol) and azeotroped with toluene. Under argon,THF (30 mL) was added and the solution was cooled in an ice-bathfollowed by dropwise addition of lithium aluminum hydride (1 M solutionin THF, 6.02 mL). After 5 min, the ice bath was removed and the reactionwas stirred at rt for 1 h. The reaction was quenched with a few drops ofmethanol, followed by addition of sat. Rochelle's salt solution andEtOAc. The mixture was stirred for 15 min and the organic layer wasseparated, washed with brine, dried with MgSO4 and concentrated. Theresidue was purified by silica gel chromatography using a gradient of0-50% EtOAc in hexanes to provide the title compound (2.63 g, 88%) as awhite solid.

Step F: tert-Butyl(4-((3a′S,3b′S,5a′R,9a′R,9b′S,9c′R,10a′R,10b′R)-5a′-hydroxy-9a′,10b′-dimethyltetradecahydro-9c′H-dispiro[[1,3]dioxolane-2,1′-cyclopenta[1,2]phenanthro[3,4-b]oxirene-7′,2″-[1,3]dioxolane]-9c′-yl)phenyl)(methyl)carbamate

3-Chlorobenzenecarboperoxoic acid (75%, 3.57 g, 15.5 mmol) was added toa solution of tert-butyl(4-((5′R,8′S,9′R,10′R,13′R,14′S)-5′-hydroxy-10′,13′-dimethyl-1′,4′,5′,6′,7′,8′,9′,10′,13′,14′,15′,16′-dodecahydro-2′H-dispiro[[1,3]dioxolane-2,3′-cyclopenta[a]phenanthrene-17′,2″-[1,3]dioxolan]-11′-yl)phenyl)(methyl)carbamate(Step E) (1.93 g, 3.88 mmol) in DCM (60 mL). The reaction was stirred atrt for 20 h and treated with sat. NaHCO₃, and extracted with EtOAc. Theorganic layer was separated, washed with brine, dried over MgSO₄ andconcentrated in vacuo. The residue was purified by silica gelchromatography using a gradient of 0-45% EtOAc in hexanes to provide themore polar isomer (530 mg, 27%) as the desired product. The less polarisomer was also isolated (910 mg, 46%).

Step G:(5′R,8′S,9′R,10′R,11′S,12′S,13′R,14′S)-10′,13′-Dimethyl-11′-(4-(methylamino)phenyl)dodecahydro-2′H-dispiro[[1,3]dioxolane-2,3′-cyclopenta[a]phenanthrene-17′,2″-[1,3]dioxolane]-5′,12′(4′H)-diol

An oven-dried 3-necked 250 mL flask was fitted with a cold fingercondenser and an argon balloon. Both the 3-necked flask and the coldfinger were cooled with dry ice in acetone. Liquid ammonia from a supplytank was condensed into the flask until the desired volume of 25 mL wasreached. Lithium metal (109 mg, 13.7 mmol) was added and the solutionchanged to a dark blue color. The dry ice bath was removed briefly for 2min to speed up the dissolving process of lithium, then the flask wasreturned to the cooling bath. After about 4 min, a solution oftert-butyl(4-((3a′S,3b′S,5a′R,9a′R,9b′S,9c′R,10a′R,10b′R)-5a′-hydroxy-9a′,10b′-dimethyltetradecahydro-9c′H-dispiro[[1,3]dioxolane-2,1′-cyclopenta[1,2]phenanthro[3,4-b]oxirene-7,2′-[1,3]dioxolane]-9c′-yl)phenyl)(methyl)carbamate(1.05 g, 1.72 mmol) (Step F) in THF (20 ml) was added dropwise overabout 5 min. The reaction was continued for 50 min and its colorremained dark blue. At this point, 0.5 mL of ethanol was added, stirredfor 1 min, then the cooling bath was removed and water was added slowlyto quench the reaction. EtOAc was added and ammonia was allowed toevaporate. The reaction mixture was extracted with EtOAc and washed withbrine. The organic layer was dried, concentrated and the residue waspurified by silica gel chromatography to give 715 mg of desired product(81%). m/z (ESI, +ve ion) 514.4 (M+H)⁺.

Step H.(5′R,8′S,9′R,10′R,11′S,12′S,13′R,14′S)-11′-(4-(Dimethylamino)phenyl)-10′,13′-dimethyldodecahydro-2′H-dispiro[[1,3]dioxolane-2,3′-cyclopenta[a]phenanthrene-17′,2″-[1,3]dioxolane]-5′,12′(4′H)-diol

A flask was charged with(5′R,8′S,9′R,10′R,11′S,12′S,13′R,14'S)-10′,13′-dimethyl-11′-(4-(methylamino)phenyl)dodecahydro-2′H-dispiro[[1,3]dioxolane-2,3′-cyclopenta[a]phenanthrene-17′,2″-[1,3]dioxolane]-5′,12′(4′H)-diol(609 mg, 1.19 mmol) (Step G) and DCM (12 mL) was added, followed byacetic acid (0.68 mL, 11.9 mmol). Then formaldehyde (0.45 mL, 5.93 mmol)was added and the mixture was stirred for 6 min. Sodiumtriacetoxyborohydride (276 mg, 1.30 mmol) was added. The reaction wasstirred for 1 h and quenched with saturated NaHCO₃ and extracted withEtOAc. The organic layer was dried, concentrated and purified by silicagel chromatography to give 575 mg of the title compound (92%). m/z (ESI,+ve ion) 528.3 (M+H)⁺.

Step I.(8S,9R,10R,11S,12S,13R,14S)-11-(4-(Dimethylamino)phenyl)-12-hydroxy-10,13-dimethyl-1,6,7,8,9,10,11,12,13,14,15,16-dodecahydro-3H-cyclopenta[a]phenanthrene-3,17(2H)-dione

A flask was charged with(5′R,8′S,9′R,10′R,11′S,12′S,13′R,14′S)-11′-(4-(dimethylamino)phenyl)-10′,13′-dimethyldodecahydro-2′H-dispiro[[1,3]dioxolane-2,3′-cyclopenta[a]phenanthrene-17′,2″-[1,3]dioxolane]-5′,12′(4′H)-diol(Step H) (940 mg, 1.78 mmol) and acetone (26 mL) was added, followed by4 N hydrogen chloride (1.78 mL, 7.13 mmol). The resulting clear mixturewas stirred at rt for 2 h. The reaction was quenched with sat. NaHCO₃and extracted with EtOAc. The EtOAc layer was washed with brine, driedover MgSO₄ and concentrated in vacuo. The residue was purified by silicagel chromatography to give 411 mg (55%) of desired product. m/z (ESI,+ve ion) 422.3 (M+H)⁺.

Step J.O-((8S,9R,10R,12S,13R,14S)-11-(4-(Dimethylamino)phenyl)-10,13-dimethyl-3,17-dioxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-12-yl)1H-imidazole-1-carbothioate

A flask was charged with(8S,9R,10R,11S,12S,13R,14S)-11-(4-(dimethylamino)phenyl)-12-hydroxy-10,13-dimethyl-1,6,7,8,9,10,11,12,13,14,15,16-dodecahydro-3H-cyclopenta[a]phenanthrene-3,17(2H)-dione(Step I) (411 mg, 0.97 mmol) and azeotroped with toluene. DCM (24 mL)was added, followed by triethylamine (0.27 ml, 1.95 mmol) anddi(imidazol-1-yl)methanethione (2.8 g, 15.6 mmol). After the reactionwas stirred under argon at rt for 4 days, it was quenched with dilutedHCl and the crude was extracted with EtOAc. The organic layer was washedwith brine twice, dried, and concentrated. The residue was purified bysilica gel chromatography to give the title compound (427 mg, 82%).

Step K.(8S,9R,10R,11S,13S,14S)-11-(4-(Dimethylamino)phenyl)-10,13-dimethyl-1,6,7,8,9,10,11,12,13,14,15,16-dodecahydro-3H-cyclopenta[a]phenanthrene-3,17(2H)-dione

A flask was chargedO-((8S,9R,10R,12S,13R,14S)-11-(4-(dimethylamino)phenyl)-10,13-dimethyl-3,17-dioxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-12-yl)1H-imidazole-1-carbothioate (Step J) (420 mg, 0.79 mmol) and flushedwith argon. Toluene (19 mL) was added, followed by tributyltin hydride(0.42 mL, 1.58 mmol). After the reaction was refluxed for 3 h, it wascooled to rt and concentrated. The residue was purified by silica gelchromatography to give the title compound (168 mg, 84%) as a colorlessoil. m/z (ESI, +ve ion) 406.4 (M+H)⁺.

Step L.(8S,9R,10R,11S,13S,14S)-11-(4-(Dimethylamino)phenyl)-3-ethoxy-10,13-dimethyl-1,2,7,8,9,10,11,12,13,14,15,16-dodecahydro-17H-cyclopenta[a]phenanthren-17-one

A flask was charged with(8S,9R,10R,11S,13S,14S)-11-(4-dimethylamino)phenyl)-10,13-dimethyl-1,6,7,8,9,10,11,12,13,14,15,16-dodecahydro-3H-cyclopenta[a]phenanthrene-3,17(2H)-dione(Step K) (210. mg, 0.52 mmol) and azeotroped with toluene.p-Toluenesulfonic acid monohydrate (118.2 mg, 0.62 mmol) was added tothe flask and the flask was flushed with Argon. Ethanol (8 mL) wasadded, and the reaction was cooled in an ice-bath. Triethyl orthoformate(0.26 mL, 1.55 mmol) was added. The reaction was stirred in the ice-bathfor 1 h. Triethylamine (0.72 mL) was added to neutralize the acid. Thereaction was concentrated and then directly purified by silica gelchromatography to give the desired mono-ketone (66 mg, 29%). Theremaining over-protected and alternate mono-protected products wererecycled through hydrolysis with HCl as in Step I. m/z (ESI, +ve ion)434.4 (M+H)⁺.

Step M.(8S,9R,10R,11S,13S,14S,17S)-11-(4-(Dimethylamino)phenyl)-17-hydroxy-17-(3-methoxyprop-1-yn-1-yl)-10,13-dimethyl-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one

A flask was charged with 3-methoxyprop-1-yne (0.1 mL, 1.2 mmol) and THF(2 mL). The reaction mixture was cooled at −78° C. and n-butyllithium(0.71 mL, 1.14 mmol) was added dropwise. The resulting mixture wasstirred at −78° C. for 10 min and then added to a solution of(8S,10R,11S,13S,14S)-11-[4-(dimethylamino)phenyl]-3-ethoxy-10,13-dimethyl-1,2,7,8,9,11,12,14,15,16-decahydrocyclopenta[a]phenanthren-17-one(Step L) (29 mg, 0.07 mmol) in THF (2 mL) at −78° C. After the reactionwas stirred at −78° C. for 60 min, it was quenched with saturated NH₄Cland extracted with EtOAc. The organic layer was dried, filtered andconcentrated. The residue was dissolved in THF (1.5 mL), 1.2 mL water(1.2 mL) and 4N HCl (0.75 mL) and the solution was stirred at rt for 1h. The solution was quenched with saturated NaHCO₃ solution andextracted with EtOAc. The organic layer was concentrated and the residuewas purified by the preparative reverse phase HPLC to give the titlecompound as the TFA salt (23 mg, 72%). ¹H NMR (400 MHz, CHLOROFORM-d) δppm 7.05-7.25 (2H, m), 6.48-6.75 (2H, m), 5.68 (1H, d, J=1.17 Hz),4.09-4.22 (2H, m), 3.41-3.45 (1H, m), 3.40 (3H, s), 2.94 (6H, s), 2.45(1H, m), 2.20-2.35 (4H, m), 2.10-2.15 (1H, m) 1.85-2.00 (3H, m), (3H, brd, J=4.53 Hz), 1.68-1.85 (2H, m), 1.36-1.53 (4H, m), 1.02 (3H, s), 0.90(3H, s); m/z (ESI, +ve ion)=476.4 [M+H]⁺.

Example 2. Compound 9.(8R,9S,10R,11S,13S,14S,17)-11-(4-(Diethylamino)phenyl)-17-(3,3-dimethylbut-1-yn-1-yl)-17-hydroxy-13-methyl-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one

Step A.(8S,13S,14S)-13-Methyl-1,2,4,6,7,8,12,13,14,15,16,17-dodecahydrospiro[cyclopenta[a]phenanthren-3,2′-[1,3]dioxolan]-17-ol

To a solution of(8S,13S,14S)-13-methyl-1,4,6,7,8,12,13,14,15,16-decahydrospiro[cyclopenta[a]phenanthrene-3,2′-[1,3]dioxolan]-17(2H)-one(100 g, 318 mmol) in THF (500 mL) and MeOH (50 mL) was added sodiumborohydride (6.14 g, 159 mmol) in portions at 0° C. The mixture wasstirred at 0° C. for 30 min and then rt for 1 h. After the TLC showedthat the starting material disappeared, the reaction was quenched with 2mL of sat. NaHCO₃ solution and concentrated to remove MeOH. The residuewas dissolved in EtOAc, the organic phase was washed with sat. NaHCO₃solution, brine, dried over anhydrous Na₂SO₄, and concentrated underreduced pressure to give the title compound (99.5 g, 100% yield) as acolorless oil. The crude material was used for next reaction withoutfurther purification. m/z (ESI, +ve ion)=317.3 [M+H]⁺.

Step B.(5′R,8′S,10′R,13′S,14′S)-13′-Methyl-1′,2′,7′,8′,12′,13′,14′,15′,16′,17′-decahydro-4′H,6′H-spiro[[1,3]dioxolane-2,3′-[5,10]epoxycyclopenta[a]phenanthren]-17′-ol

To a solution of(8S,13S,14S)-13-methyl-1,2,4,6,7,8,12,13,14,15,16,17-dodecahydrospiro[cyclopenta[a]phenanthrene-3,2′-[1,3]dioxolan]-17-ol(43.0 g, 136 mmol, Step A) in DCM (320 mL) at 0° C. was added Na₂HPO₄(9.65 g, 68.0 mmol), followed by 1,1,1,3,3,3-hexafluoropropan-2-onetrihydrate (11.2 mL, 81.5 mmol) and H₂O₂ (35% aqueous solution, 34.2 mL,408 mmol). The mixture was stirred at 0° C. for 10 min and then at rtfor 3 h. 10% Sodium thiosulfate solution (200 mL) was slowly added at 0°C. and the mixture was stirred at rt for 30 min and extracted with DCM(300 mL). The organic phase was washed with brine, dried over anhydrousNa₂SO₄, and concentrated to provide the title compound (43.0 g) as a 4:1mixture of epoxides as a white solid. The crude material was used fornext step without further purification.

Step C.(8S,11R,13S,14S)-11-(4-(Diethylamino)phenyl)-17-hydroxy-13-methyl-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one

A dried flask was charged with magnesium chips (2.04 g, 83.9 mmol) and acrystal of iodine. The flask was flushed with Ar and heated briefly witha heat gun and then put into a 60° C. of oil bath. A small portion of asolution of 4-bromo-N,N-diethylaniline (18.5 g, 81.2 mmol, azeotropedwith toluene beforehand) in THF (80 mL) was added (about 5 mL). Afterthe iodine color disappeared, the remaining solution was added dropwisefor 20 min and the mixture was continued to stir at 60° C. for 2 h.

The Grignard reagent prepared above was cooled down to rt and added to asolution of(5′R,8′S,10′R,13′S,14′S)-13′-methyl-1′,2′,7′,8′,12′,13′,14′,15′,16′,17-decahydro-4′H,6′H-spiro[[1,3]dioxolane-2,3′-[5,10]epoxycyclopenta[a]phenanthren]-17-ol(9.00 g, 27.1 mmol, azeotroped with toluene, Step B) and copper(I)iodide (2.60 g, 13.5 mmol) in THF (100 mL) at 0° C. The resultingmixture was allowed to warm up to rt and stir for 1 h. The reaction wasquenched (sat. aq. NH₄Cl), extracted (2×EtOAc), and washed (brine). Thecombined organic layer was dried (Na₂SO₄) and concentrated under reducedpressure. Purification of the residue by combi-flash (220 g SiO₂, 20% to80% EtOAc/hexanes) provided(5R,8S,11R,13S,14S)-11-(4-(diethylamino)phenyl)-13-methyl-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydrospiro[cyclopenta[a]phenanthrene-3,2′-[1,3]dioxolane]-5,17(4H)-diol(6.50 g, 13.5 mmol, 50% yield) as an off-white foam.

A solution of(5R,8S,11R,13S,14S)-11-(4-(diethylamino)phenyl)-13-methyl-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydrospiro[cyclopenta[a]phenanthrene-3,2′-[1,3]dioxolane]-5,17(4H)-diol(6.50 g, 13.5 mmol) in 70% Acetic acid in water (109 mL) was stirred at55° C. for 1 h. The reaction was concentrated under reduced pressure toremove most of AcOH. Then the residue was diluted (EtOAc), basified(sat. aq. NaHCO₃), extracted (2×EtOAc), and washed (brine). The combinedorganic layer was dried (Na₂SO₄), and concentrated under reducedpressure. Purification of the residue by combi-flash (220 g SiO₂, 20% to60% EtOAc/hexanes) gave the title compound (6.80 g, 16.2 mmol, 80%yield) as a white solid. ¹H NMR (400 MHz, CHLOROFORM-d) δ 6.98 (d,J=8.33 Hz, 2H), 6.54-6.66 (m, 2H), 5.75 (s, 1H), 4.28 (d, J=6.72 Hz,1H), 3.66 (br t, J=8.04 Hz, 1H), 3.25-3.38 (m, 4H), 2.68-2.83 (m, 1H),2.32-2.61 (m, 7H), 1.98-2.16 (m, 2H), 1.60-1.74 (m, 3H), 1.30-1.49 (m,3H), 1.14 (t, J=7.09 Hz, 6H), 0.48 (s, 3H).

Step D.(8S,9R,11S,13S,14S)-11-(4-(Diethylamino)phenyl)-17-hydroxy-13-methyl-1,2,4,6,7,8,9,11,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one

Under Ar, lithium (283 g, 40.8 mmol) in pieces was added to liquidammonia (157 mL) at −78° C. When the color changed to dark blue, asolution(8S,11R,13S,14S)-11-(4-(diethylamino)phenyl)-17-hydroxy-13-methyl-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one(4.50 g, 10.7 mmol, Step C) in THF (100 mL) was added over 15 min (keptthe internal temperature below −60° C.), followed by addition of asolution of tert-butanol (2.50 mL, 25.7 mmol) in THF (50 mL) over 1 min(dark purple color remained after adding). The reaction was quenched bysolid ammonium chloride (12.0 g, 225 mmol). Both dry ice bath and coldfinger condenser were removed and most ammonia was allowed to evaporateby stirring the slurry at rt for 1 h. The reaction was diluted(saturated aq. NH₄Cl), and extracted (2×EtOAc). The combined organiclayer was washed (saturated aq. NH₄Cl), dried (Na₂SO₄) and concentratedunder reduced pressure. Purification of the residue by combi-flash (220g SiO₂, 20% to 60% EtOAc/hexanes) provided the title compound (2.60 g,6.17 mmol, 58% yield). m/z (ESI, +ve ion)=422.3 [M+H]⁺.

Step E.(8R,9S,10R,11S,13S,14S)-11-(4-(Diethylamino)phenyl)-17-hydroxy-13-methyl-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one

To a solution of(8S,9R,11S,13S,14S)-11-[4-(diethylamino)phenyl]-17-hydroxy-13-methyl-2,4,6,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-one(2.60 g, 6.17 mmol, Step D) in toluene (50 mL) was added4-methylbenzenesulfonic acid hydrate (3.52 g, 18.5 mmol) under Ar andthe resulting solution was heated at 80° C. for 1 h. The reaction wasquenched with TEA (3 mL), cooled, diluted (EtOAc and sat aq. NaHCO₃),and extracted (2×EtOAc). The combined organic layer was washed (brine),dried (Na₂SO₄), and concentrated under reduced pressure. Purification ofthe residue by combi flash (120 g, 40% to 60% EtOAc/hexanes) providedthe title compound (1.50 g, 3.56 mmol, 58% yield) as a white foam. m/z(ESI, +ve ion)=422.3 [M+H]⁺.

Step F.(8R,9S,10R,11S,13S,14S)-11-(4-(Diethylamino)phenyl)-13-methyl-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydrospiro[cyclopenta[a]phenantrene-3,2′-[1,3]dithiolan]-17-ol

To a solution of(8R,9S,10R,11S,13S,14S)-11-(4-(diethylamino)phenyl)-17-hydroxy-13-methyl-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one(1.50 g, 3.56 mmol, Step E) and p-toluenesulfonic acid monohydrate (1.35g, 7.11 mmol) in acetic acid (15 mL) was added ethane-1,2-dithiol (3.00mL, 35.6 mmol). After the solution was stirred at rt for 1 h under Ar,the reaction was quenched (ice-cold 2.5 N aq. NaOH) and extracted(2×EtOAc). The combined organic layer was washed (brine), dried (MgSO4),and concentrated under reduced pressure. Purification of the residue bycombi-flash (120 g SiO₂, 20% to 40% EtOAc/hexanes) provided the titlecompound (740 mg, 1.49 mmol, 42% yield) as a white solid. ¹H NMR (400MHz, CHLOROFORM-d) δ 7.21 (d, J=8.62 Hz, 2H), 6.58 (d, J=8.92 Hz, 2H),5.61 (a, 1H), 3.56 (br t, J=7.97 Hz, 1H), 3.25-3.41 (m, 7H), 3.16-3.25(m, 2H), 2.42-257 (m, 1H), 2.27 (td, J=3.27, 13.63 Hz, 1H), 1.93-2.15(m, 6H), 1.81-1.92 (m, 2H), 1.50-1.73 (m, 2H), 1.21-1.38 (m, 2H),1.08-1.18 (m, 7H), 0.79-1.05 (m, 3H), 0.54 (s, 3H); m/z (ESI, +veion)=498.4 [M+H]⁺.

Step G.(8R,9S,10R,11S,13S,14S)-11-(4-(Diethylamino)phenyl)-13-methyl-1,6,7,8,9,10,11,12,13,14,15,16-dodecahydrospiro[cyclopenta[a]phenanthrene-3,2′-[1,3]dithiolan]-17(2H)-one

To a solution of(8R,9S,10R,11S,13S,14S)-11-(4-(diethylamino)phenyl)-13-methyl-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydrospiro[cyclopenta[a]phenanthrene-3,2′-[1,3]dithiolan]-17-ol(740 mg, 1.49 mmol, Step F) in toluene (15 mL) was added cyclohexanone(0.44 mL, 4.28 mmol) and aluminum propan-2-olate (410 mg, 2.00 mmol)successively. After the reaction was heated to 105° C. for 4 h, it wascooled to rt and quenched with saturated aqueous Rochelle's saltsolution. The mixture was stirred for 10 min and extracted (2×EtOAc).The combined organic layer was washed (brine), dried (MgSO₄), andconcentrated under reduced pressure. Purification of the residue bycombi-flash (40 g SiO₂, 10% to 50% EtOAc/hexanes) provided the titlecompound (430 mg, 0.87 mmol, 58% yield) as a white solid. ¹H NMR (400MHz, CHLOROFORM-d) δ 7.20 (d, J=7.63 Hz, 2H), 6.57 (d, J=8.92 Hz, 2H),5.60-5.70 (s, 1H), 3.24-3.41 (m, 8H), 3.16-3.24 (m, 1H), 2.37-258 (m,2H), 2.33 (m, 1H), 1.93-2.20 (m, 6H), 1.83 (dt, J=2.78, 13.08 Hz, 1H),1.66-1.76 (m, 2H), 1.50-1.66 (m, 2H), 1.25-1.37 (m, 3H), 1.02-1.21 (m,7H), 0.67 (s, 3H); m/z (ESI, +ve ion)=496.4 [M+H]⁺.

Step H.(8R,9S,10R,11S,13S,14S,17S)-11-(4-(Diethylamino)phenyl)-17-(3,3-dimethylbut-1-yn-1-yl)-13-methyl-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydrospiro[cyclopenta[a]phenanthrene-3,2′-[1,3]dithiolan]-17-ol

To a solution of isopropylmagnesium chloride (2 M solution in THF, 0.76mL, 1.51 mmol) in THF (1 mL) was added 3,3-dimethylbut-1-yne (0.19 mL,0.61 mmol) at 0° C. dropwise under Ar. After the solution was stirred atrt for 10 min, the mixture was stirred at 50° C. for 1 h (with acondenser). The Grignard reagent was cooled to 0° C. and a solution of(8R,9S,10R,11S,13S,14S)-11-[4-(diethylamino)phenyl]-13-methyl-spiro[1,2,6,7,8,9,10,11,12,14,15,16-dodecahydrocyclopenta[a]phenanthrene-3,2′-1,3-dithiolane]-17-one(100 mg, 0.20 mmol, Step G) in THF (2 mL) was added dropwise. After thereaction was stirred at 0° C. for 30 min, it was allowed to warm to rtand stirred overnight. The reaction was quenched (sat. aq. NH₄Cl) andextracted (2×EtOAc). The combined organic layers were washed (brine),dried (MgSO₄), and concentrated under reduced pressure. Purification ofthe residue by combi-flash (12 g SiO₂, 15% to 35% EtOAc/hexanes)provided the title compound (110 mg, 0.19 mmol, 94% yield) as a whitesolid; m/z (ESI, +ve ion)=578.5 [M+H]⁺.

Step I.(8R,9S,10R,11S,13S,14S,17S)-11-(4-(Diethylamino)phenyl)-17-(3,3-dimethylbut-1-yn-1-yl)-17-hydroxy-13-methyl-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one

To a solution of(8R,9S,10R,11S,13S,14S,17S)-11-(4-(diethylamino)phenyl)-17-(3,3-dimethylbut-1-yn-1-yl)-13-methyl-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydrospiro[cyclopenta[a]phenanthrene-3,2-[1,3]dithiolan]-17-ol(110 mg, 0.19 mmol, Step H) in acetic acid (4 mL) was added glyoxylicacid monohydrate (876 mg, 9.52 mmol) at rt and the mixture was stirredat rt for 10 min. Then 4 N HCl in water (0.86 mL, 3.43 mmol) was addedand the resulting solution was stirred at rt for 20 h. The reaction wasquenched (sat. aq. NaHCO₃), extracted (2×EtOAc), and washed (brine). Thecombined organic layers were dried (Na₂SO₄) and concentrated underreduced pressure. Purification of the residue with combi-flash (12 gSiO₂, 20% to 40% EtOAc/hexanes) provided the title compound (33 mg,0.066 mmol, 38% yield) as a white foam. ¹H NMR (400 MHz, CHLOROFORM-d) δ7.23 (br d, J=8.33 Hz, 2H), 6.60 (br d, J=8.77 Hz, 2H), 5.86 (br s, 1H),3.33 (br d, J=6.87 Hz, 5H), 2.86 (br s, 1H), 2.53 (br d, J=15.05 Hz,1H), 2.38 (m, 1H), 2.01-2.30 (m, 5H), 1.92 (m, 3H), 1.71 (br s, 1H),1.46-1.64 (m, 5H), 1.21-1.28 (s, 9H), 1.17 (m, 7H), 0.67 (s, 3H); m/z(ESI, +ve ion)=502.4 [M+H]⁺.

Examples 3-10 were prepared by procedures similar to those described inExample 2, substituting 4-bromo-N,N-diethylaniline with the appropriatebromide in Step C and 3,3-dimethylbut-1-yne with the appropriate alkynein Step H.

Example 3. Compound 1.(8R,9S,10R,11S,13S,14S,17S)-17-(3,3-Dimethylbut-1-yn-1-yl)-17-hydroxy-13-methyl-11-(4-(pyrrolidin-1-yl)phenyl)-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one

¹H NMR (400 MHz, CHLOROFORM-d) δ 7.24-7.29 (m, 2H), 6.50 (d, J=8.77 Hz,2H), 5.86 (s, 1H), 3.22-3.41 (m, 4H), 2.86 (m, 1H), 2.53 (m, 1H), 2.37(m, 2H), 2.21-2.29 (m, 1H), 1.99-2.20 (m, 7H), 1.89-1.96 (m, 2H),1.61-1.81 (m, 6H), 1.23-1.43 (m, 11H), 1.01-1.21 (m, 1H), 0.68 (s, 3H);m/z (ESI, +ve ion)=500.5 [M+H]⁺.

Example 4. Compound 3.(8R,9S,10R,11S,13S,14S,17S)-11-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-17-(3,3-dimethylbut-1-yn-1-yl)-17-hydroxy-13-methyl-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one

¹H NMR (400 MHz, CHLOROFORM, d) δ 6.93 (d, J=1.90 Hz, 1H), 6.83-6.91 (m,1H), 6.78 (d, J=8.33 Hz, 1H), 5.87 (s, 1H), 4.23-4.32 (m, 4H), 3.33 (brt, J=5.85 Hz, 1H), 2.86 (br s, 1H), 2.53 (br d, J=14.18 Hz, 1H),2.36-2.42 (m, 1H), 2.11-2.29 (m, 4H), 2.02-2.09 (m, 2H), 1.84-1.99 (m,3H), 1.69-1.81 (m, 1H), 1.44-1.55 (m, 2H), 1.23-1.41 (m, 1H), 1.01-1.15(m, 1H) 0.67 (s, 3H); m/z (ESI, +ve ion)=489.4 [M+H]⁺.

Example 5. Compound 5.(8R,9S,10R,11S,13S,14S,17S)-11-(Benzo[d][1,3]dioxol-5-yl)-17-(3,3-dimethylbut-1-yn-1-yl)-17-hydroxy-13-methyl-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 6.86-6.94 (2H, m), 6.74 (1H, d,J=8.0 Hz), 5.94-6.00 (2H, m), 5.87 (1H, s), 3.35 (1H, br t, J=6.0 Hz),2.80-2.90 (1H, m), 2.50-2.57 (1H, m), 2.36-2.42 (1H, m), 2.24-2.35 (2H,m), 1.96-2.23 (5H, m), 1.87-1.95 (3H, m), 1.69-1.80 (1H, m), 1.44-1.55(2H, m), 1.38 (1H, td, J=12.0, 5.7 Hz), 1.26-1.33 (1H, m), 1.24 (9H, s),1.11 (1H, br dd, J=12.1, 3.7 Hz), 0.68 (3H, s); m/z (ESI, +ve ion)=475.4[M+H]⁺.

Example 6. Compound 4.(8R,9S,10R,11S,13S,14S,17S)-17-Hydroxy-11-(4-(isopropyl(methyl)amino)phenyl)-17-(3-methoxy-3-methylbut-1-yn-1-yl)-13-methyl-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one

¹H NMR (400 MHz, CHLOROFORM-d) δ 7.25 (br d, J=8.6 Hz, 2H), 6.71 (br d,J=8.77 Hz, 2H), 5.86 (s, 1H), 4.08 (td, J=6.56, 13.34 Hz, 1H), 3.37 (s,3H), 3.33 (br t, J=5.41 Hz, 1H), 2.85 (br m, 11H), 2.73 (s, 3H), 2.53(br d, J=14.32 Hz, 1H), 2.18-2.43 (m, 4H), 1.89-2.16 (m, 6H), 1.67-1.80(m, 2H), 1.37-1.55 (m, 8H), 1.26 (dt, J=5.55, 11.40 Hz, 1H), 1.05-1.21(m, 7H), 0.69 (s, 3H); m/z (ESI, +ve ion)=518.5 [M+H]⁺.

Example 7. Compound 7.(8R,9S,10R,11S,13S,14S,17S)-17-(3,3-Dimethylbut-1-yn-1-yl)-17-hydroxy-13-methyl-11-(4-morpholinophenyl)-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one

¹H NMR (400 MHz, CHLOROFORM-d) δ 7.33 (br d, J=8.33 Hz, 2H), 6.84 (br d,J=7.45 Hz, 2H), 5.87 (s, 1H), 3.88 (br s, 4H), 3.26-3.48 (m, 1H), 3.17(br s, 4H), 2.82 (br s, 1H), 2.54 (br d, J=14.03 Hz, 1H), 2.33-2.46 (m,1H), 2.03-2.31 (m, 5H) 1.82-1.99 (m, 3H), 1.67-1.80 (m, 1H), 1.45-1.65(m, 3H), 1.21-1.42 (m, 11H), 1.07-1.18 (m, 1H), 0.64 (s, 3H); m/z (ESI,+ve ion)=516.3 [M+H]⁺.

Example 8. Compound 6.(8R,9S,10R,11S,13S,14S,17S)-11-(4-(Dimethylamino)phenyl)-17-(3,3-dimethylpent-1-yn-1-yl)-17-hydroxy-13-methyl-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.27 (2H, s), 6.67 (2H, br d, J=6.4Hz), 5.86 (1H, s), 3.34 (1H, br s), 2.95 (3H, br), 2.95 (3H, br), 2.83(1H, br d, J=10.8 Hz), 2.49-2.57 (1H, m), 2.37 (1H, td, J=14.1, 4.3 Hz),2.27 (2H, dt, J=16.3, 3.9 Hz), 2.19 (1H, ddd, J=13.8, 9.6, 5.7 Hz),2.02-2.14 (3H, m), 1.87-1.99 (3H, m), 1.69-1.78 (1H, m), 1.63 (1H, s),1.48-1.54 (2H, m), 1.44 (2H, q, J=7.6 Hz), 1.33-1.41 (1H, m), 1.22-1.31(1H, m), 1.19 (3H, s), 1.19 (3H, s), 1.10 (1H, br d, J=12.0 Hz), 0.99(3H, t, J=7.6 Hz), 0.66 (3H, s); m/z (ESI, +ve ion)=488.5 [M+H]⁺.

Example 9. Compound 11.(8R,9S,10R,11S,13S,14S,17S)-11-(4-(tert-Butyl(methyl)amino)phenyl)-17-(3,3-dimethylbut-1-yn-1-yl)-17-hydroxy-13-methyl-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one

¹H NMR (400 MHz, CHLOROFORM-d) δ 7.25-7.30 (m, 2H), 7.01-7.05 (m, 2H),5.85 (s, 1H), 3.37 (s, 1H), 2.81-2.93 (m, 1H), 2.74 (s, 3H), 2.50 (m,1H), 2.31-2.41 (m, 1H), 1.98-231 (m, 5H), 1.86-1.96 (m, 3H), 1.64-1.74(m, 1H), 1.43-1.53 (m, 2H), 1.16-138 (m, 12H), 1.04-1.14 (m, 10H), 0.56(s, 3H); MS (ESI)=516.5 [M+H]+.

Example 10. Compound 2.(8R,9S,10R,11S,13S,14S,17S)-17-(3,3-Dimethylbut-1-yn-1-yl)-17-hydroxy-11-(4-(isopropyl(methyl)amino)phenyl)-13-methyl-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.23 (2H, br d, J=83 Hz), 6.71 (2H,br d, J=8.3 Hz), 5.86 (1H, s), 4.04-4.11 (1H, m), 3.33 (1H, br s), 2.86(1H, br s), 2.72 (3H, s), 2.53 (1H, br d, J=14.3 Hz), 2.33-2.43 (1H, m),2.07-2.31 (5H, m), 2.03 (1H, br s), 1.88-1.97 (3H, m), 1.68-1.78 (1H,m), 1.63 (1H, s), 1.46-1.55 (2H, m), 1.34-1.42 (1H, m), 1.26-130 (1H,m), 1.24 (9H, s), 1.17 (3H, d, J=5.6 Hz), 1.15 (3H, d, J=5.6 Hz),1.06-1.12 (1H, m), 0.67 (3H, s); m/z (ESI, +ve ion)=502.4 [M+H]⁺.

Example 11. Compound 10.(8R,9S,10R,11S,13S,14S,17S)-17-(3,3-Dimethylbut-1-yn-1-yl)-17-hydroxy-11-(4-(isopropylamino)phenyl)-13-methyl-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one

Step A.(8S,11R,13S,14S)-11-(4-Aminophenyl)-17-hydroxy-13-methyl-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one

The title compound was prepared from(5′R,8′S,10′R,13′S,14′S)-13′-methyl-1′,2′,7′,8′,12′,13′,14′,15′,16′,17′-decahydro-4′H,6′H-spiro[[1,3]dioxolane-2,3′-[5,10]epoxycyclopenta[a]phenanthren]-17′-ol(Example 2, Step B) by a procedure similar to that described in Example2, Step C, substituting (4-(bis(trimethylsilyl)amino)phenyl)magnesiumbromide for (4-(diethylamino)phenyl)magnesium bromide.

Step B. tert-Butyl(4-((8S,11R,13S,14S)-17-hydroxy-13-methyl-3-oxo-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-11-yl)phenyl)carbamate

To a flask charged with(8S,11R,13S,14S)-11-(4-aminophenyl)-17-hydroxy-13-methyl-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one(4.00 g, 11.0 mmol, azeotroped with toluene, Step A) were addeddi-tert-butyl dicarbonate (12.0 g, 55.0 mmol) and MeCN (72 mL). Thereaction was stirred overnight. Then the solid was filtered and rinsed(v/v=5/1, hep/EtOAc). The filtrate was purified by combi-flash (80 gSiO₂, 25% to 50% EtOAc/hexanes) to provide the title compound (4.90 g,10.6 mmol, 96% yield) as a yellow solid.

Step C.(8R,9S,10R,11S,13S,14S)-11-(4-Aminophenyl)-13-methyl-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydrospiro[cyclopenta[a]phenanthrene-3,2′-[1,3]dithiolan]-17-ol

The title compound was prepared from tert-butyl(4-((8S,11R,13S,14S)-17-hydroxy-13-methyl-3-oxo-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-11-yl)phenyl)carbamate(Step B) by procedures similar to those described in Example 2, Steps D,E, and F.

Step D.(8R,9S,10R,11S,13S,14S)-11-(4-(Isopropylamino)phenyl)-13-methyl-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydrospiro[cyclopenta[a]phenanthrene-3,2′-[1,3]dithiolan]-17-ol

To a solution of acetone (86.4 uL, 1.18 mmol) and(8′R,11′S,13′S,14′S)-11′-(4-aminophenyl)-13′-methyl-spiro[1,3-dithiolane-2,3′-2,6,7,8,9,10,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthrene]-17′-ol(19.2 mL, 0.12 mmol, Step C) in DCE (1.1 mL) was added sodiumtriacetoxyborohydride (62.4 mg, 0.29 mmol) at rt. After the reaction wasstirred at rt, it was basified (sat. aq. NaHCO₃), extracted (2×DCM), andwashed (water). The combined organic layer was dried (Na₂SO₄) andconcentrated under reduced pressure. Purification of the residue bycombi-flash (12 g SiO₂, 30% to 50% EtOAc/hexanes) provided the titlecompound (51.0 mg, 0.105 mmol, 90% yield) as an off white solid. m/z(ESI, +ve ion)=486.4 [M+H]⁺.

Step E.(8R,9S,10R,11S,13S,14S,17S)-17-(3,3-Dimethylbut-1-yn-1-yl)-17-hydroxy-11-(4-(isopropylamino)phenyl)-13-methyl-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one

The title compound was prepared from(8R,9S,10R,11S,13S,14S)-11-(4-(isopropylamino)phenyl)-13-methyl-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydrospiro[cyclopenta[a]phenanthrene-3,2′-[1,3]dithiolan]-17-ol(Step D) by procedures similar to those described in Example 2, Steps G,H, and I.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.19 (d, J=7.89 Hz, 2H), 6.52 (d,J=7.75 Hz, 2H), 5.85 (s, 1H), 3.57-3.64 (m, 1H), 3.28-3.32 (m, 1H),2.79-2.86 (m, 1H), 2.49-2.55 (m, 1H), 2.30-2.40 (m, 1H), 2.01-2.29 (m,6H), 1.86-1.97 (m, 3H), 1.69-1.74 (m, 1H), 1.63 (s, 1H), 1.37-1.55 (m,3H), 1.30-1.40 (m, 1H), 1.20-1.28 (m, 15H), 0.66 (s, 3H); m/z (ESI, +veion)=488.4 [M+H]⁺.

Example 12. Compound 13.(8R,9S,10R,11S,13S,14S,17S)-11-(4-Aminophenyl)-17-(3,3-dimethylbut-1-yn-1-yl)-17-hydroxy-13-methyl-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one

Step A. tert-Butyl(4-((8R,9S,10R,11S,13S,14S)-17-hydroxy-13-methyl-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydrospiro[cyclopenta[a]phenanthrene-3,2′-[1,3]dithiolan]-11-yl)phenyl)carbamate

A flask was charged with(8R,9S,10R,11S,13S,14S)-11-(4-Aminophenyl)-13-methyl-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydrospiro[cyclopenta[a]phenanthrene-3,2′-[1,3]dithiolan]-17-ol(358 mg, 0.81 mmol, azeotroped with toluene, Example 11, Step C),di-tert-butyl dicarbonate (885 mg, 4.05 mmol) and MeCN (6 mL) was added.After the reaction was stirred overnight, the solid was filtered andrinsed with 5:1 heptane:EtOAc. The filtrate was purified by combi-flash(40 g SiO₂, 25% to 50% EtOAc/hexanes) to provide the title compound (420mg, 0.780 mmol, 95% yield).

Step B. tert-Butyl(4-((8R,9S,10R,11S,13S,14S,17S)-17-(3,3-dimethylbut-1-yn-1-yl)-17-hydroxy-13-methyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-11-yl)phenyl)carbamate

The title compound was prepared from tert-butyl(4-((8R,9S,10R,11S,13S,14S)-17-hydroxy-13-methyl-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydrospiro[cyclopenta[a]phenanthrene-3,2-[1,3]dithiolan]-11-yl)phenyl)carbamate(Step A) by procedures similar to those described in Example 2, Steps G,H, and I.

Step C.(8R,9S,10R,11S,13S,14S,17S)-11-(4-Aminophenyl)-17-(3,3-dimethylbut-1-yn-1-yl)-17-hydroxy-13-methyl-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one

A flask was charged with tert-butyl(4-((8R,9S,10R,11S,13S,14S,17S)-17-(3,3-dimethylbut-1-yn-1-yl)-17-hydroxy-13-methyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-11-yl)phenyl)carbamate(39 mg, 0.07 mmol, Step B) in acetone (1 mL), followed by addition of 4N HCl in dioxane (0.09 mL, 0.36 mmol). After the resulting clear mixturewas stirred at rt for 5 h, it was quenched with sat NaHCO₃ solution andthen extracted with EtOAc. The organic layer was washed with brine,dried over anhydrous sodium sulfate, and concentrated. The crude productwas purified by combi-flash (4 g SiO₂, 0 to 70% EtOAc/hexanes) toprovide the title compound (8.0 mg, 0.018 mmol, 25%) as an off-whitesolid. ¹H NMR (400 MHz, DICHLOROMETHANE-d2) δ ppm 7.12 (d, J=8.33 Hz,2H), 6.49-6.55 (d, 2H), 5.71 (s, 1H), 3.22 (br t, J=5.92 Hz, 1H),2.71-2.77 (m, 1H), 2.40-2.45 (m, 1H), 2.23-2.33 (m, 1H), 1.91-2.19 (m,6H), 1.70-1.85 (m, 3H), 1.54-1.69 (m, 2H), 1.34-1.48 (m, 3H), 1.22-1.34(m, 1H), 1.14 (s, 9H), 0.54 (s, 3H); m/z (ESI, +ve ion)=446.3 [M+H]⁺.

Example 13. Compounds 14 and 15.(8R,9S,10R,11S,13S,14S,17S)-17-(3,3-dimethylbut-1-yn-1-yl)-11-(3-fluoro-4-isopropylamino)phenyl)-17-hydroxy-13-methyl-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one(14) and(8R,9S,10R,11S,13S,14S,17S)-17-(3,3-Dimethylbut-1-yn-1-yl)-11-(3-fluoro-4-(isopropyl(methyl)amino)phenyl)-17-hydroxy-13-methyl-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one(15)

A dry flask was charged with(8R,9S,11S,13S,14S,17S)-17-(3,3-dimethylbut-1-ynyl)-17-hydroxy-11-[4-[isopropyl(methy)amino]phenyl]-13-methyl-1,2,6,7,8,9,10,11,12,14,15,16-dodecahydrocyclopenta[a]phenanthren-3-one(300 mg, 0.60 mmol, Example 10) and DCM (8 mL). The flask was cooled to0° C. and 1-fluoro-2,4,6-trimethylpyridinium trifluoromethanesulfonate(294 mg, 1.02 mmol) was added. After the reaction was stirred at 0° C.for 60 min, it was warmed up to rt and stirred for another 30 min. Thereaction mixture was quenched with NaHCO₃ solution (6 ml) and extractedwith EtOAc (200 ml). The organic layer was washed with brine, dried overanhydrous sodium sulfate, and concentrated. The residue was purified bycombi-flash eluting with 1:9 EtOAc/hexanes to provide a mixture of 14and 15. The mixture was purified by preparative reverse-phase HPLC(gradient elution of 10% to 90% MeCN in water, which both solventscontain 0.1% formic acid, 30 min method) to give(8R,9S,10R,11S,13S,14S,17S)-17-(3,3-dimethylbut-1-yn-1-yl)-11-(3-fluoro-4-(isopropyl(methyl)amino)phenyl)-17-hydroxy-13-methyl-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one(15) as the first eluting isomer and(8R,9S,10R,11S,13S,14S,17S)-17-(3,3-dimethylbut-1-yn-1-yl)-11-(3-fluoro-4-(isopropylamino)phenyl)-17-hydroxy-13-methyl-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one(14) as the second eluting isomer.

Compound 14: ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 6.99-7.22 ((m, 2H),6.62 (t, J=8.62 Hz, 1H), 5.87 (s, 1H), 3.47-3.75 (m, 1H), 3.22-3.46 (m,1H), 2.76-2.86 (br dd, J=3.00, 1.68 Hz, 1H), 2.530-2.58 (br d, J=14.32Hz, 1H), 2.34-2.43 (m, 1H), 2.21-2.35 (m, 2H), 2.14-2.211 (m, 1H),2.05-2.14 (m, 1H), 2.02-2.05 (m, 1H), 1.83-2.00 (m, 2H), 1.68-1.78 (m,1H), 1.64-1.68 (m, 1H), 1.45-1.55 (m, 3H), 1.32-1.42 (m, 1H), 1.24-1.27(d, J=4 Hz, 3H), 1.20-1.24 (m, 12H), 1.05-1.15 (m, 2H), 0.57-0.68 (m,3H); m/z (ESI, +ve ion) 506.5 (M+H)⁺.

Compound 15: ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 6.98-7.17 (m, 2H),6.84 (t, J=8.84 Hz, 1H), 5.87 (s, 1H), 3.66-3.81 (m, 1H), 3.35 (br t,J=5.12 Hz, 1H), 2.84 (br dd, J=3.29, 1.53 Hz, 1H), 2.69 (s, 3H),2.50-2.59 (m, 1H), 2.38-2.43 (m, 1H), 2.22-2.36 (m, 2H), (d, J=1.97,1.06 Hz, 1H), 2.10-2.22 (m, 2H), 2.01-2.12 (m, 2H), 1.84-2.00 (m, 2H),1.69-1.81 (m, 1H), 1.66 (s, 1H), 1.43-1.56 (m, 2H), 1.34-1.44 (m, 1H),1.25-1.33 (m, 3H), 1.24 (9 s, H), 1.07-1.18 (m, 6H), 0.63 (s, 3H); m/z(ESI, +ve ion) 520.4 (M+H)⁺.

Example 14. Compound 8.(8R,9S,10R,11S,13S,14S,16R,17S)-17-(3,3-Dimethylbut-1-yn-1-yl)-17-hydroxy-11-(4-(isopropyl(methyl)amino)phenyl)-13,16-dimethyl-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-oneor(8R,9S,10R,11S,13S,14S,16S,17S)-17-(3,3-dimethylbut-1-yn-1-yl)-17-hydroxy-11-(4-(isopropyl(methyl)amino)phenyl)-13,16-dimethyl-1,2,6,7,89,10,11,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one

Step A.(8R,9S,10R,11S,13S,14S,16R)-11-(4-(Isopropyl(methyl)amino)phenyl)-13,16-dimethyl-1,6,7,8,9,10,11,12,13,14,15,16-dodecahydrospiro[cyclopenta[a]phenanthrene-3,2′-[1,3]dithiolan]-17(2H)-oneor(8R,9S,10R,11S,13S,14S,16S)-11-(4-(isopropyl(methyl)amino)phenyl)-13,16-dimethyl-1,6,7,8,9,10,11,12,13,14,15,16-dodecahydrospiro[cyclopenta[a]phenanthrene-3,2′-[1,3]dithiolan]-17(2H)-one

To a solution of(8S,13S,14S)-13-methyl-1,4,6,7,8,12,13,14,15,16-decahydrospiro[cyclopenta[a]phenanthren-3,2′-[1,3]dioxolan]-17(2H)-one(8.00 g, 25.4 mmol, an intermediate of Example 10 in Step G) and 3 ml ofDMPU in THF (50 mL) at −45° C. was added[bis(trimethylsilyl)amino]lithium (50.9 mL, 50.9 mmol). After 30 minstirring, iodomethane (7.92 mL, 127 mmol) was added. The reaction wasstirred at −20° C. for 1 h and was quenched with sat. NH₄Cl, extractedwith EtOAc, washed with brine, dried over Na₂SO₄, and concentrated underreduced pressure. The residue was purified by a combi-flash (10-20%EtOAc/hexanes) to give the title compound (6.70 g, 20.4 mmol, 80%yield).

Step B.(8R,9S,10R,11S,13S,14S,16R,17S)-17-(3,3-Dimethylbut-1-yn-1-yl)-17-hydroxy-11-(4-(isopropyl(methyl)amino)phenyl)-13,16-dimethyl-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-oneor(8R,9S,10R,11S,13S,14S,16S,17S)-17-(3,3-dimethylbut-1-yn-1-yl)-17-hydroxy-11-(4-(isopropyl(methyl)amino)phenyl)-13,16-dimethyl-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one

The title compound was prepared from(8R,9S,10R,11S,13S,14S,16R)-11-(4-(isopropyl(methyl)amino)phenyl)-13,16-dimethyl-1,6,7,8,9,10,11,12,13,14,15,16-dodecahydrospiro[cyclopenta[a]phenanthrene-3,2′-[1,3]dithiolan]-17(2H)-oneor(8R,9S,10R,11S,13S,14S,16S)-11-(4-(isopropyl(methyl)amino)phenyl)-13,16-dimethyl-1,6,7,8,9,10,11,12,13,14,15,16-dodecahydrospiro[cyclopenta[a]phenanthrene-3,2′-[1,3]dithiolan]-17(2H)-one(Step A) by procedures similar to those described in Example 2, Steps Hand I.

¹H NMR (400 MHz, CHLOROFORM-d) δ 7.24 (d, J=8.77 Hz, 2H), 6.71 (d,J=8.92 Hz, 2H), 5.85 (s, 1H), 4.02-4.13 (M, 1H), 3.27-3.37 (m, 1H),2.77-2.92 (m, 1H), 2.67-2.73 (m, 3H), 2.47-2.58 (m, 1H), 2.36 (m, 1H),1.85-2.31 (m, 8H), 1.57-1.75 (m, 1H), 1.44-1.57 (m, 2H), 1.19-1.30 (m,11H), 1.16 (dd, J=5.12, 6.58 Hz, 6H), 1.11 (m, 4H), 0.73 (s, 3H); m/z(ESI, +ve ion)=516.5 [M+H]⁺.

Example 15. Compound 21.(8S,9R,10R,11S,13S,14S,17S)-17-(Cyclopropylethynyl)-17-hydroxy-11-(4-(isopropyl(methy)amino)phenyl)-10,13-dimethyl-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one

Example 15 was prepared from(8′S,9′S,10′R,13′R,14′S)-10′,13′-dimethyl-1′,4′,7′,8′,9′,10′,13′,14′,15′,16′-decahydro-2′H-dispiro[[1,3]dioxolane-2,3′-cyclopenta[a]phenanthrene-17′,2″-[1,3]dioxolan]-11′-yl1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate (Example 1, Step B) byprocedures similar to those described in Example 1, Steps C-M,substituting formaldehyde with acetone in Step H and substituting3-methoxyprop-1-yne with ethynylcyclopropane in Step M. ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm 7.20-7.40 (m, 2H), 6.64 (d, J=8.77 Hz, 2H), 5.68 (d,J=1.32 Hz, 1H), 4.05 ((m, 1H), 3.50 (s, 1H), 3.40 (m, 1H), 2.71 (s, 3H),2.50 (m, 1H), 2.20-2.40 (m, 5H), 2.10-2.20 (m, 2H), 1.95 (m, 3H), 1.73(m, 2H), 1.43 (m, 3H), 1.30 (m, 2H), 1.16 (dd, J=6.58, 1.17 Hz, 6H),1.02 (s, 3H), 0.87 (s, 3H), 0.74-0.84 (m, 2H), 0.60-0.73 (m, 2H); m/z(ESI, +ve ion)=486.4 [M+H]⁺.

Example 16. Compound 26.(8S,9R,10R,11S,13S,14S,17S)-11-(4-Aminophenyl)-17-hydroxy-10,13-dimethyl-17-(prop-1-yn-1-yl)-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one

Example 16 was prepared from(8′S,9′S,10′R,13′R,14′S)-10′,13′-dimethyl-1′,4′,7′,8′,9′,10′,13′,14′,15′,16′-decahydro-2′H-dispiro[[1,3]dioxolane-2,3′-cyclopenta[a]phenanthrene-17′,2″-[1,3]dioxolan]-11′-yl1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate (Example 1, Step B) byprocedures similar to those described in Example 1, Steps C-G,substituting (4-((tert-butoxycarbonyl)(methyl)amino)phenyl)boronic acidwith (4-((tert-butoxycarbonyl)aminophenyl)boronic acid in Step C, andfollowed by procedures similar to those described in Example 1, StepsI-M, substituting 3-methoxyprop-1-yne with prop-1-yne in Step M. ¹H NMR(400 MHz, CHLOROFORM-d) δ ppm 7.26-7.05 (br s, 2H), 6.54-6.62 ((m, 2H),5.69 (d, J=1.32 Hz, 1H), 3.59 (br s, 2H), 3.41 (t, J=5.55 Hz, 1H),2.46-2.59 (m, 1H), 2.1-2.33 (m, 7H), 1.86-1.99 (m, 3H), 1.89 (s, 3H),1.64-1.81 (m, 3H), 1.36-1.56 (m, 3H), 1.10-1.23 (m, 1H), 1.03 (s, 3H),0.87 (s, 3H); m/z (ESI, +ve ion)=418.3[M+H]⁺.

Example 17. Compound 30.(8S,9R,10R,11S,13S,14S,17S)-17-Hydroxy-11-(4-(isopropylamino)phenyl)-10,13-dimethyl-17-(prop-1-yn-1-yl)-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one

Example 17 was prepared from8S,9R,10R,11S,13S,14S,17S)-11-(4-aminophenyl)-17-hydroxy-10,13-dimethyl-17-(prop-1-yn-1-yl)-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one(Example 16) by procedure similar to that described in Example 1, StepH, substituting formaldehyde with acetone. ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm 7.25-7.05 (br s, 2H), 6.46 (d, J=8.77 Hz, 2H), 5.68(d, J=1.17 Hz, 1H), 3.61 (quin, J=6.29 Hz, 1H), 3.33-3.43 (m, 2H),2.47-2.56 ((m, 1H), 2.10-2.34 (m, 7H), 1.86-1.99 (m, 3H), 1.89 (s, 3H),1.70-1.84 (m, 3H), 1.36-1.51 (m, 3H), 1.22 (d, J=4.0 Hz, 1H), 1.21 (d,J=4.0 Hz, 1H), 1.09-1.18 (m, 1H), 1.03 (s, 3H) 0.88 (s, 3H); m/z (ESI,+ve ion)=460.4 [M+H]⁺.

Example 18. Compound 31.(8S,9R,10R,11S,13S,14S,17S)-11-(4-1H-Pyrrol-1-yl)phenyl)-17-hydroxy-10,13-dimethyl-17-(prop-1-yn-1-yl)-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-cylopenta[a]phenanthren-3-one

Example 18 was prepared from8S,9R,10R,11S,13S,14S,17S)-11-(4-aminophenyl)-17-hydroxy-10,13-dimethyl-17-(prop-1-yn-1-yl)-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one(Example 16) by procedure similar to that described in Example 1, StepH, substituting formaldehyde with 2,5-dimethoxytetrahydrofuran. ¹H NMR(400 MHz, CHLOROFORM-d) δ ppm 7.40-7.65 (br s, 2H), 7.23-7.27 (m, 2H),7.10 (t, J=2.19 Hz, 2H), 6.35 (t, J=2.19 Hz, 2H), 5.71 (d, J=1.02 Hz,1H), 3.55 (br t, J=5.85 Hz, 1H), 2.54 (d, J=14.47, 4.53 Hz, 1H),2.15-2.39 (m, 7H), 1.94-2.01 (m, 3H), 1.91 (s, 3H), 1.70-1.85 (m, 3H),1.41-1.58 (m, 3H), 1.12-1.23 (m, 1H), 1.7 (s, 3H), 0.86 (s, 1H); m/z(ESI, +ve ion)=468.4 [M+H]⁺.

II. Biological Evaluation Example A: In Vivo GR Luciferase Assay CellLine: CHO/GR/MMTV Luciferase

Culture Media: DMEM (with phenol red)+10% FBSAssay Media: DMEM (without phenol red)+10% CSS

A 1×10 cm plate of cells was split into 2×15 cm plates in Assay Media(CSS). After 4 days, the cells in the Assay Media were collected andcounted.

Antagonist Assay: 1.5×10⁴ cells per well were plated in a 384-well whitewalled TC plate in 20 ul of Assay Media containing 12.5 nM Dexamethasone(final concentration=10 nM).

The plates were covered with film to avoid evaporation and placed in aTC incubator. Media/drug dilutions were prepared in Assay Media in96-well sterile plates.

100 ul of Assay Media was distributed in aliquots into 96-well plateswith an 8-Channel pipette (20-200 ul). 0.5 ul of 1000× concentration ofcompounds were added to the plates with 8-Channel pipette (0.5-10 ul).The plates were shaken for 15 seconds to mix. The film was removed fromthe 384-well plates with assay cells. 5 ul of media/drug dilutions wereadded to appropriate wells. The plates were covered with film to avoidevaporation and placed in a TC incubator overnight. After 16-18 h in theincubator, the plates were removed and sat at room temperature for 10minutes to equilibrate. The Reagent Dispenser was setup to distribute 25ul aliquots of OneGlo Luciferase Reagent (at room temperature) to eachwell of the 384-well plate using standard cassette. After OneGlo wasadded to the plates, the plates were shaken briefly, then incubated inthe dark at room temperature for about 3 minutes. The plates were readusing a Tecan or Promega luminometer.

The ability of the compounds disclosed herein to inhibit GR activity wasquantified and the respective IC₅₀ value was determined. Table 3provides the cellular IC₅₀ values of various substituted steroidalcompounds disclosed herein.

TABLE 3 GR IC₅₀ No. (nM) 1 A 2 A 3 A 4 A 5 A 6 A 7 A 8 A 9 A 10 A 11 A12 B 13 A 14 B 15 A 16 B 17 B 18 A 19 B 20 A 21 A 22 A 23 B 24 A 25 A 26B 27 A 28 B 29 A 30 B 31 A 32 B Note: Cellular assay IC₅₀ data aredesignated within the following ranges: A: ≤100 nM B: >100 nM

Example B: In Vitro AR Agonism Assay

The AR agonism assay was done in the LNAR reporter cell line which hasoverexpressed AR and 4XARE-Luc genes. This cell line is sensitive toeven minor partial AR agonism activity in hormone-deprived media (CSS).The assays were done in RPMI (without phenol red)+10% CSS using 6000LNAR cells/well in 384-well plates and compounds were incubated withcells in 370 C incubator for 18-24 hrs. OneGlo reagent (25 uL/well) wasadded and plates were read with luminometer within 3 minutes.

Mifepristone shows strong partial AR agonism in concentrations as low as10 nM, and is known to significantly promote CRPC growth both in vivoand in vitro. To gauge the AR partial agonism activity, Mifepristone isincluded as a standard in the assay. AR agonism assay results arequantified by determining the ratio of the maximum response ofindividual compounds to the maximum response of Mifepristone(arbitrarily set to 1). Values of Table 4 are reported as RelativeMaximum Response to Mifepristone. This general trend of AR agonism wasshown for the class of compounds described herein.

TABLE 4 Relative Maximum Response to No. Mifepristone 1 A 2 A 4 A 6 A 7A 8 A 10 A 11 A 14 A 17 A 18 A 19 A 20 A 21 A 22 A 25 A 32 A Note: ARagonism response assay data relative maximum response to Mifepristone isdesignated within the following ranges: A: ≤0.4 B: >0.4

1.-55. (canceled)
 56. A method for treating a hypercortisolism disorderin a subject, the method comprising administering to the subject atherapeutically effective amount of a compound of Formula (III), or apharmaceutically acceptable salt thereof:

wherein ring A is heteroaryl, aryl, cycloalkyl, or heterocyclyl; R¹ is—NR^(4a)R^(5a); each R² is independently —NR⁴R⁵, optionally substitutedalkylNR⁴R⁵, halo, —OR⁶, —OH, optionally substituted alkyl, haloalkyl,optionally substituted carbocyclyl, optionally substitutedcarbocyclylalkyl, optionally substituted heteroalkyl, optionallysubstituted heterocyclyl, optionally substituted heterocyclylalkyl,optionally substituted hydroxyalkyl, —C(O)R⁶, —C(O)OR⁶, —C(O)NR⁴R⁵,—OC(O)OR⁶, —OC(O)NR⁴R⁵, —S(O)₂NR⁴R⁵, —S(O)₂R⁷, —S(O)R⁷, —SR⁷,—NR⁴S(O)₂NR⁴R⁵, —CN, —CO₂H, or —NO₂; or R¹ and R² on adjacent atoms aretaken together with the atoms to which they are attached to form anoptionally substituted heterocycle; R³ is optionally substituted C₂₋₈alkyl, halo, haloalkyl, optionally substituted carbocyclyl, optionallysubstituted carbocyclylalkyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, optionally substitutedheteroalkyl, optionally substituted aryl, optionally substitutedheteroaryl, —Si(R⁶)₃, —OR⁶, or —S(O)₂R⁷; R^(4a) is C₂₋₈ alkyl,optionally substituted carbocyclyl, optionally substituted aryl,optionally substituted heterocyclyl, optionally substituted heteroaryl,—S(O)₂R⁷, —C(O)N(R¹³)₂, —C(O)R⁶, or —C(O)OR⁶; R^(5a) is —H, optionallysubstituted alkyl, haloalkyl, optionally substituted carbocyclyl,optionally substituted aryl, optionally substituted heterocyclyl,optionally substituted heteroaryl, —S(O)₂R⁷, —C(O)N(R¹³)₂, —C(O)R⁶, or—C(O)OR⁶; or R^(4a) and R^(5a) are taken together with the N atom towhich they are attached to form an optionally substituted heterocycle;R⁴ and R⁵ are each independently —H, optionally substituted alkyl,haloalkyl, optionally substituted carbocyclyl, optionally substitutedaryl, optionally substituted heterocyclyl, optionally substitutedheteroaryl, —S(O)₂R⁷, —C(O)N(R¹³)₂, —C(O)R⁶, or —C(O)OR⁶; or R⁴ and R⁵are taken together with the N atom to which they are attached to form asubstituted or unsubstituted heterocycle; each R⁶ is independentlyoptionally substituted alkyl, haloalkyl, optionally substitutedcarbocyclyl, optionally substituted aryl, optionally substitutedheterocyclyl, or optionally substituted heteroaryl; R⁷ is optionallysubstituted alkyl, haloalkyl, optionally substituted carbocyclyl,optionally substituted heteroalkyl, optionally substituted aryl,optionally substituted aralkyl, optionally substituted heterocyclyl, oroptionally substituted heteroaryl; R⁸ and R⁹ are each independently —H,optionally substituted alkyl, haloalkyl, halo, optionally substitutedcarbocyclyl, optionally substituted carbocyclylalkyl, optionallysubstituted heteroalkyl, optionally substituted heterocyclyl, optionallysubstituted heterocyclylalkyl, —OH, —S(O)₂R⁷, —C(O)₂H, —C(O)R⁶, or—C(O)OR⁶; or R⁸ and R⁹ are taken together with the atom to which theyare attached to form a substituted or unsubstituted ring containing 0-2heteroatoms selected from the group consisting of —O—, —NH—, —NR⁶—, —S—,and —S(O)₂—; R¹⁰ and R¹¹ are each independently —H, optionallysubstituted alkyl, halo, haloalkyl, optionally substituted carbocyclyl,optionally substituted carbocyclylalkyl, optionally substitutedheteroalkyl, optionally substituted heterocyclyl, optionally substitutedheterocyclylalkyl, —OH, —S(O)₂R⁷, —C(O)₂H, —C(O)R⁶, or —C(O)OR⁶; or R¹⁰and R¹¹ are taken together with the atom to which they are attached toform a substituted or unsubstituted ring containing 0-2 heteroatomsselected from the group consisting of —O—, —NH—, —NR⁶—, —S—, and—S(O)₂—; R¹² is hydrogen, optionally substituted alkyl, haloalkyl,hydroxy, halo, optionally substituted carbocyclyl, optionallysubstituted carbocyclylalkyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, or optionally substitutedheteroalkyl; each R¹³ is independently H, optionally substituted alkyl,haloalkyl, optionally substituted carbocyclyl, optionally substitutedheteroalkyl, optionally substituted aryl, optionally substitutedaralkyl, optionally substituted heterocyclyl, or optionally substitutedheteroaryl; and n is 0, 1, 2, 3, or
 4. 57. The method of claim 56,wherein in the compound of Formula (III), or a pharmaceuticallyacceptable salt thereof, R¹² is methyl.
 58. The method of claim 56,wherein in the compound of Formula (III), or a pharmaceuticallyacceptable salt thereof, R¹² is H.
 59. The method of claim 56, whereinin the compound of Formula (III), or a pharmaceutically acceptable saltthereof, ring A is monocyclic heteroaryl or monocyclic aryl.
 60. Themethod of claim 56, wherein in the compound of Formula (III), or apharmaceutically acceptable salt thereof, ring A is phenyl.
 61. Themethod of claim 56, wherein in the compound of Formula (III), or apharmaceutically acceptable salt thereof, R^(4a) is C₂₋₈ alkyl.
 62. Themethod of claim 61, wherein in the compound of Formula (III), or apharmaceutically acceptable salt thereof, R^(4a) is ethyl, i-propyl, ort-butyl.
 63. The method of claim 56, wherein in the compound of Formula(III), or a pharmaceutically acceptable salt thereof, R^(5a) is —H,optionally substituted alkyl, or haloalkyl.
 64. The method of claim 56,wherein in the compound of Formula (III), or a pharmaceuticallyacceptable salt thereof, n is 0, 1, or
 2. 65. The method of claim 56,wherein in the compound of Formula (III), or a pharmaceuticallyacceptable salt thereof, each R² is independently —NR⁴R⁵, halo, —OR⁶,alkyl, fluoroalkyl, carbocyclyl, heteroalkyl, heterocyclyl, —S(O)₂NR⁴R⁵,or —S(O)₂R⁷.
 66. The method of claim 56, wherein in the compound ofFormula (III), or a pharmaceutically acceptable salt thereof, R³ isoptionally substituted C₂₋₈ alkyl, haloalkyl, or optionally substitutedcarbocyclyl.
 67. The method of claim 66, wherein in the compound ofFormula (III), or a pharmaceutically acceptable salt thereof, R³ is CF₃,t-butyl, or cyclopropyl.
 68. The method of claim 56, wherein in thecompound of Formula (III), or a pharmaceutically acceptable saltthereof, R³ is t-butyl.
 69. The method of claim 56, wherein in thecompound of Formula (III), or a pharmaceutically acceptable saltthereof, R⁸ and R⁹ are —H.
 70. The method of claim 56, wherein in thecompound of Formula (III), or a pharmaceutically acceptable saltthereof, R¹⁰ and R¹¹ are each —H.
 71. The method of claim 56, whereinthe compound of Formula (III), or a pharmaceutically acceptable saltthereof, has the structure of Formula (IIIa):


72. A method for treating a hypercortisolism disorder in a subject, themethod comprising administering to the subject a therapeuticallyeffective amount of a compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.
 73. The method of claim56, wherein the hypercortisolism disorder in the subject is refractoryCushing's syndrome.